Apparatus and method for noninvasive measurement of analytes from the conjunctiva using mid-infrared radiation

ABSTRACT

Utilization of a contact device placed on the eye in order to detect physical and chemical parameters of the body as well as the non-invasive delivery of compounds according to these physical and chemical parameters, with signals being transmitted continuously as electromagnetic waves, radio waves, infrared and the like. One of the parameters to be detected includes non-invasive blood analysis utilizing chemical changes and chemical products that are found in the conjunctiva and in the tear film. A transensor mounted in the contact device laying on the cornea or the surface of the eye is capable of evaluating and measuring physical and chemical parameters in the eye including non-invasive blood analysis. The system utilizes eye lid motion and/or closure of the eye lid to activate a microminiature radio frequency sensitive transensor mounted in the contact device. The signal can be communicated by wires or radio telemetered to an externally placed receiver. The signal can then be processed, analyzed and stored. Several parameters can be detected including a complete non-invasive analysis of blood components, measurement of systemic and ocular blood flow, measurement of heart rate and respiratory rate, tracking operations, detection of ovulation, detection of radiation and drug effects, diagnosis of ocular and systemic disorders and the like.

This application is a divisional application of application U.S. Ser.No. 10/359,254, filed Feb. 6, 2003, now U.S. Pat. No. 7,041,063, whichis a divisional application of U.S. Ser. No. 09/790,653, filed Feb. 23,2001, now U.S. Pat. No. 6,544,193, all of which are incorporated hereinin their entirety by reference.

FIELD OF THE INVENTION

The present invention includes a contact device for mounting on a partof the body to measure bodily functions and to treat abnormal conditionsindicated by the measurements.

BACKGROUND OF THE INVENTION

The present invention relates to a tonometer system for measuringintraocular pressure by accurately providing a predetermined amount ofapplanation to the cornea and detecting the amount of force required toachieve the predetermined amount of applanation. The system is alsocapable of measuring intraocular pressure by indenting the cornea usinga predetermined force applied using an indenting element and detectingthe distance the indenting element moves into the cornea when thepredetermined force is applied, the distance being inverselyproportional to intraocular pressure. The present invention also relatesto a method of using the tonometer system to measure hydrodynamiccharacteristics of the eye, especially outflow facility.

The tonometer system of the present invention may also be used tomeasure hemodynamics of the eye, especially ocular blood flow andpressure in the eye's blood vessels. Additionally, the tonometer systemof the present invention may be used to increase and measure the eyepressure and. evaluate, at the same time, the ocular effects of theincreased pressure.

Glaucoma is a leading cause of blindness worldwide and, although it ismore common in adults over age 35, it can occur at any age. Glaucomaprimarily arises when intraocular pressure increases to values which theeye cannot withstand.

The fluid responsible for pressure in the eye is the aqueous humor. Itis a transparent fluid produced by the eye in the ciliary body andcollected and drained by a series of channels (trabecular meshwork,Schlemm's canal and venous system). The basic disorder in most glaucomapatients is caused by an obstruction or interference that restricts theflow of aqueous humor out of the eye. Such an obstruction orinterference prevents the aqueous humor from leaving the eye at a normalrate. This pathologic condition occurs long before there is a consequentrise in intraocular pressure. This increased resistance to outflow ofaqueous humor is the major cause of increased intraocular pressure inglaucoma-stricken patients.

Increased pressure within the eye causes progressive damage to the opticnerve. As optic nerve damage occurs, characteristic defects in thevisual field develop, which can lead to blindness if the disease remainsundetected and untreated. Because of the insidious nature of glaucomaand the gradual and painless loss of vision associated therewith,glaucoma does not produce symptoms that would motivate an individual toseek help until relatively late in its course when irreversible damagehas already occurred. As a result, millions of glaucoma victims areunaware that they have the disease and face eventual blindness. Glaucomacan be detected and evaluated by measuring the eye's fluid pressureusing a tonometer and/or by measuring the eye fluid outflow facility.Currently, the most frequently used way of measuring facility of outflowis by doing indentation tonography. According to this technique, thecapacity for flow is determined by placing a tonometer upon the eye. Theweight of the instrument forces aqueous humor through the filtrationsystem, and the rate at which the pressure in the eye declines with timeis related to the ease with which the fluid leaves the eye.

Individuals at risk for glaucoma and individuals who will developglaucoma generally have a decreased outflow facility. Thus, themeasurement of the outflow facility provides information which can helpto identify individuals who may develop glaucoma, and consequently willallow early evaluation and institution of therapy before any significantdamage occurs.

The measurement of outflow facility is helpful in making therapeuticdecisions and in evaluating changes that may occur with time, aging,surgery, or the use of medications to alter intraocular pressure. Thedetermination of outflow facility is also an important research tool forthe investigation of matters such as drug effects, the mechanism ofaction of various treatment modalities, assessment of the adequacy ofantiglaucoma therapy, detection of wide diurnal swings in pressure andto study the pathophysiology of glaucoma.

There are several methods and devices available for measuringintraocular pressure, outflow facility, and/or various otherglaucoma-related characteristics of the eye. The following patentsdisclose various examples of such conventional devices and methods:

PATENT NO. PATENTEE 5,375,595 Sinha et al. 5,295,495 Maddess 5,251,627Morris 5,217,015 Kaye et al. 5,183,044 Nishio et al. 5,179,953 Kursar5,148,807 Hsu 5,109,852 Kaye et al. 5,165,409 Coan 5,076,274 Matsumoto5,005,577 Frenkel 4,951,671 Coan 4,947,849 Takahashi et al. 4,944,303Katsuragi 4,922,913 Waters, Jr. et al. 4,860,755 Erath 4,771,792 Seale4,628,938 Lee 4,305,399 Beale 3,724,263 Rose et al. 3,585,849 Grolman3,545,260 Lichtenstein et al.

Still other examples of conventional devices and/or methods aredisclosed in Morey, Contact Lens Tonometer, RCA Technical Notes, No.602, December 1964; Russell & Bergmanson, Multiple Applications of theNCT: An Assessment of the Instrument's Effect on IOP, Ophthal. Physiol.Opt., Vol. 9, April 1989, pp. 212-214; Moses & Grodzki, ThePneumatonograph: A Laboratory Study, Arch. Ophthalmol., Vol. 97, March1979, pp. 547-552; and C. C. Collins, Miniature Passive PressureTransensor for Implanting in the Eye, IEEE Transactions on Bio-medicalEngineering, April 1967, pp. 74-83.

In general, eye pressure is measured by depressing or flattening thesurface of the eye, and then estimating the amount of force necessary toproduce the given flattening or depression: Conventional tonometrytechniques using the principle of applanation may provide accuratemeasurements of intraocular pressure, but are subject to many errors inthe way they are currently being performed. In addition, the presentdevices either require professional assistance for their use or are toocomplicated, expensive or inaccurate for individuals to use at home. Asa result, individuals must visit an eye care professional in order tocheck their eye pressure. The frequent self-checking of intraocularpressure is useful not only for monitoring therapy and self-checking forpatients with glaucoma, but also for the early detection of rises inpressure in individuals without glaucoma and for whom the elevatedpressure was not detected during their office visit.

Pathogens that cause severe eye infection and visual impairment such asherpes and adenovirus as well as the virus that causes AIDS can be foundon the surface of the eye and in the tear film. These microorganisms canbe transmitted from one patient to another through the tonometer tip orprobe. Probe covers have been designed in order to prevent transmissionof diseases but are not widely used because they are not practical andprovide less accurate measurements. Tonometers which prevent thetransmission of diseases, such as the “air-puff” type of tonometer alsohave been designed, but they are expensive and provide less accuratemeasurements. Any conventional direct contact tonometers can potentiallytransmit a variety of systemic and ocular diseases.

The two main techniques for the measurement of intraocular pressurerequire a force that flattens or a force that indents the eye, called“applanation” and “indentation” tonometry respectively.

Applanation tonometry is based on the Imbert-Fick principle. Thisprinciple states that for an ideal dry, thin walled sphere, the pressureinside the sphere equals the force necessary to flatten its surfacedivided by the area of flattening. P=F/A (where P=pressure, F=force,A=area). In applanation tonometry, the cornea is flattened, and bymeasuring the applanating force and knowing the area flattened, theintraocular pressure is determined.

By contrast, according to indentation tonometry (Schiotz), a knownweight (or force) is applied against the cornea and the intraocularpressure is estimated by measuring the linear displacement which resultsduring deformation or indentation of the cornea. The linear displacementcaused by the force is indicative of intraocular pressure. Inparticular, for standard forces and standard dimensions of the indentingdevice, there are known tables which correlate the linear displacementand intraocular pressure.

Conventional measurement techniques using applanation and indentationare subject to many errors. The most frequently used technique in theclinical setting is contact applanation using Goldman tonometers. Themain sources of errors associated with this method include the additionof extraneous pressure on the cornea by the examiner, squeezing of theeyelids or excessive widening of the lid fissure by the patient due tothe discomfort caused by the tonometer probe resting upon the eye, andinadequate or excessive amount of dye (fluorescein). In addition, theconventional techniques depend upon operator skill and require that theoperator subjectively determine alignment, angle and amount ofdepression. Thus, variability and inconsistency associated with lessvalid measurements are problems encountered using the conventionalmethods and devices.

Another conventional technique involves air-puff tonometers wherein apuff of compressed air of a known volume and pressure is applied againstthe surface of the eye, while sensors detect the time necessary toachieve a predetermined amount of deformation in the eye's surfacecaused by application of the air puff. Such a device is described, forexample, in U.S. Pat. No. 3,545,260 to Lichtenstein et al. Although thenon-contact (air-puff) tonometer does not use dye and does not presentproblems such as extraneous pressure on the eye by the examiner or thetransmission of diseases, there are other problems associated therewith.Such devices, for example, are expensive, require a supply of compressedgas, are considered cumbersome to operate, are difficult to maintain inproper alignment and depend on the skill and technique of the operator.In addition, the individual tested generally complains of painassociated with the air discharged toward the eye, and due to thatdiscomfort many individuals are hesitant to undergo further measurementwith this type of device. The primary advantage of the non-contacttonometer is its ability to measure pressure without transmittingdiseases, but they are not accepted in general as providing accuratemeasurements and are primarily useful for large-scale glaucoma screeningprograms.

Tonometers which use gases, such as the pneumotonometer, have severaldisadvantages and limitations. Such device are also subject to theoperator errors as with Goldman's tonometry. In addition, this deviceuses freon gas, which is not considered environmentally safe. Anotherproblem with this device is that the gas is flammable and as with anyother aerosol-type can, the can may explode if it gets too hot. The gasmay also leak and is susceptible to changes in cold weather, therebyproducing less accurate measurements. Transmission of diseases is also aproblem with this type of device if probe covers are not utilized.

In conventional indentation tonometry (Schiotz), the main source oferrors are related to the application of a relatively heavy tonometer(total weight at least 16.5 g) to the eye and the differences in thedistensibility of the coats of the eye. Experience has shown that aheavy weight causes discomfort and raises the intraocular pressure.Moreover the test depends upon a cumbersome technique in which theexaminer needs to gently place the tonometer onto the cornea withoutpressing the tonometer against the globe. The accuracy of conventionalindentation may also be reduced by inadequate cleaning of the instrumentas will be described later. The danger of transmitting infectiousdiseases, as with any contact tonometer, is also present withconventional indentation.

A variety of methods using a contact lens have been devised, however,such systems suffer from a number of restrictions and virtually none ofthese devices is being widely utilized or is accepted in the clinicalsetting due to their limitations and inaccurate readings. Moreover, suchdevices typically include instrumented contact lenses and/or cumbersomeand complex contact lenses.

Several instruments in the prior art employ a contact lens placed incontact with the sclera (the white part of the eye). Such systems sufferfrom many disadvantages and drawbacks. The possibility of infection andinflammation is increased due to the presence of a foreign body indirect contact with a vascularized part of the eye. As a consequence, aninflammatory reaction around the device may occur, possibly impactingthe accuracy of any measurement. In addition, the level of discomfort ishigh due to a long period of contact with a highly sensitive area of theeye. Furthermore, the device could slide and therefore lose properalignment, and again, preventing accurate measurements to be taken.Moreover, the sclera is a thick and almost non-distensible coat of theeye which may further impair the ability to acquire accurate readings.Most of these devices utilize expensive sensors and complicated electriccircuitry imbedded in the lens which are expensive, difficult tomanufacture and sometimes cumbersome.

Other methods for sensing pressure using a contact lens on the corneahave been described. Some of the methods in this prior art also employexpensive and complicated electronic circuitry and/or transducersimbedded in the contact lens. In addition, some devices usepiezoelectric material in the lens and the metalization of components ofthe lens overlying the optical axis decreases the visual acuity ofpatients using that type of device. Moreover, accuracy is decreasedsince the piezoelectric material is affected by small changes intemperature and the velocity with which the force is applied. There arealso contact lens tonometers which utilize fluid in a chamber to causethe deformation of the cornea; however, such devices lack means foralignment and are less accurate, since the flexible elastic material isunstable and may bulge forward. In addition, the fluid therein has atendency to accumulate in the lower portion of the chamber, thus failingto produce a stable flat surface which is necessary for an accuratemeasurement.

Another embodiment uses a coil wound about the inner surface of thecontact lens and a magnet subjected to an externally created magneticfield. A membrane with a conductive coating is compressed against acontact completing a short circuit. The magnetic field forces the magnetagainst the eye and the force necessary to separate the magnet from thecontact is considered proportional to the pressure. This device suffersfrom many limitations and drawbacks. For example, there is a lack ofaccuracy since the magnet will indent the cornea and when the magnet ispushed against the eye, the sclera and the coats of the eye distorteasily to accommodate the displaced intraocular contents. This occursbecause this method does not account for the ocular rigidity, which isrelated to the fact that the sclera of one person's eye is more easilystretched than the sclera of another. An eye with a low ocular rigiditywill be measured and read as having a lower intraocular pressure thanthe actual eye's pressure. Conversely, an eye with a high ocularrigidity distends less easily than the average eye, resulting in areading which is higher than the actual intraocular pressure. Inaddition, this design utilizes current in the lens which, in turn, is indirect contact with the body. Such contact is undesirable. Unnecessarycost and complexity of the design with circuits imbedded in the lens anda lack of an alignment system are also major drawbacks with this design.

Another disclosed contact lens arrangement utilizes a resonant circuitformed from a single coil and a single capacitor and a magnet which ismovable relative to the resonant circuit. A further design from the samedisclosure involves a transducer comprised of a pressure sensitivetransistor and complex circuits in the lens which constitute theoperating circuit for the transistor. All three of the disclosedembodiments are considered impractical and even unsafe for placement ona person's eye. Moreover, these contact lens tonometers areunnecessarily expensive, complex, cumbersome to use and may potentiallydamage the eye. In addition none of these devices permits measurement ofthe applanated area, and thus are generally not very practical.

The prior art also fails to provide a sufficiently accurate technique orapparatus for measuring outflow facility. Conventional techniques anddevices for measuring outflow facility are limited in practice and aremore likely to produce erroneous results because both are subject tooperator, patient and instrument errors.

With regard to operator errors, the conventional test for outflowfacility requires a long period of time during which there can be notilting of the tonometer. The operator therefore must position and keepthe weight on the cornea without moving the weight and without pressingthe globe.

With regard to patient errors, if during the test the patient blinks,squeezes, moves, holds his breath, or does not maintain fixation, thetest results will not be accurate. Since conventional tonography takesabout four minutes to complete and generally requires placement of arelatively heavy tonometer against the eye, the chances of patientsbecoming anxious and therefore reacting to the mechanical weight placedon their eyes is increased.

With regard to instrument errors, after each use, the tonometer plungerand foot plate should be rinsed with water followed by alcohol and thenwiped dry with lint-free material. If any foreign material drys withinthe foot plate, it can detrimentally affect movement of the plunger andcan produce an incorrect reading.

The conventional techniques therefore are very difficult to perform anddemand trained and specialized personnel. The pneumotonograph, besideshaving the problems associated with the pneumotonometer itself, wasconsidered “totally unsuited to tonography.” (Report by the Committee onStandardization of Tonometers of the American Academy of Ophthalmology;Archives Ophthalmol., 97:547-552, 1979). Another type of tonometer (NonContact “Air Puff” Tonometer˜U.S. Pat. No. 3,545,260) was alsoconsidered unsuitable for tonography. (Ophthalmic & PhysiologicalOptics, 9(2):212-214, 1989). Presently there are no truly acceptablemeans for self-measurement of intraocular pressure and outflow facility.

In relation to an additional embodiment of the present invention, bloodis responsible not only for the transport of oxygen, food, vitamins,water, enzymes, white and red blood cells, and genetic markers, but alsoprovides an enormous amount of information in regards to the overallhealth status of an individual. The prior art related to analysis ofblood relies primarily on invasive methods such as with the use ofneedles to draw blood for further analysis and processing. Very few andextremely limited methods for non-invasive evaluating blood componentsare available.

In the prior art for example, oxygenated hemoglobin has been measurednon-invasively. The so called pulse oximeter is based on traditionalnear infrared absorption spectroscopy and indirectly measures arterialblood oxygen with sensors placed over the skin utilizing LEDs emittingat two wave lengths around 940 and 660 nanometers. As the bloodoxygenation changes, the ratio of the light transmitted by the twofrequencies changes indicating the amount of oxygenated hemoglobin inthe arterial blood of the finger tip. The present systems are notaccurate and provide only the amount of oxygenated hemoglobin in thefinger tip.

The skin is a thick layer of tissue with a thick epithelium. Theepithelium is the superficial layers of tissue and vary according to theorgan or location in the body. The skin is-thick because it is in directcontact with the environment and it is the barrier between the internalorgans and the external environment. The skin is exposed and subject toall kind of noxious external agents on a daily basis. Stratifiedsquamous keratinizing epithelium layers of the skin have a strong,virtually impermeable layer called the stratum corneum and keratin. Thekeratin that covers the skin is a thick layer of a hard and dead tissuewhich creates another strong barrier of protection against pathogenicorganisms but also creates a barrier to the proper evaluation of bodilyfunctions such as non-invasive blood analysis and cell analysis.

Another drawback in using the skin is due to the fact that thesuperficial layer of tissue covering the skin does not allow acquisitionof important information, only present in living tissue. In addition,the other main drawback in using the skin is because the blood vesselsare not easily accessible. The main vascular supply to the skin islocated deep and distant from the superficial and still keratinizedimpermeable skin layer.

Prior art attempts to use the skin and other areas of the body toperform non-invasive blood analysis, diagnostics and evaluations ofbodily functions such as oral, nasal and ear mucosa. These areas havebeen found to be unsuitable for such tasks. Moreover, placement of anobject in oral or nasal mucosa can put the user at risk of aspirationand obstructing the airway which is a fatal event.

Another drawback in using the skin is the presence of various appendagesand glands which prevent adequate measurements from being acquired suchas hair, sweat glands, and sebaceous glands with continuous outflowingof sebum. Moreover, the layers of the skin vary in thickness in a randomfashion. Furthermore, the layers of the skin are strongly attached toeach other, making the surgical implantation of any device extremelydifficult. Furthermore the skin is a highly innervated area which ishighly sensitive to painful stimuli.

In order to surgically implant a device under the skin there is need forinvasive application of anesthetic by injection around the area to beincised and the obvious risk of infection. Moreover, the structure ofthe skin creates electrical resistance and makes acquisition ofelectrical signals a much more difficult procedure.

Attempts to use electroosmosis as a flux enhancement by iontophoresiswith increased passage of fluid through the skin with application ofelectrical energy, do not provide accurate or consistent signals andmeasurements due to the skin characteristics described above.Furthermore there is a significant delay in the signal acquisition whenelectroosmosis-based systems are used on the skin because of the anatomyand physiology of the skin which is thick and has low permeability.

Previously, a watch with sensing elements in apposition to the skin hasbeen used in order to acquire a signal to measure glucose. Because ofthe unsuitable characteristics of the skin the watch has to actuallyshock the patient in order to move fluid. The fluid measured providesinconsistent, inaccurate and delayed results because of the unsuitablecharacteristics of the skin as described above. It is easy to see howunstable the watch is if one were to observe how much their own watchmoves up and down and around one=s pulse during normal use. There is nonatural stable nor consistent correct apposition of the sensor surfaceto the tissue, in this case the dead keratin layer of the thick skin.

Previously invasive means were used with tearing of the skin in the tipof the fingers to acquire whole blood, instead of plasma, for glucosemeasurement. Besides being invasive, whole blood from the fingers isused which has to be corrected for plasma levels. Plasma levels providethe most accurate evaluation of blood glucose.

The conventional way for blood analysis includes intense labor and manyexpenses using many steps including cumbersome, expensive and bulkylaboratory equipment. A qualified medical professional is required toremove blood and this labor is certainly costly. The professionalsexpose themselves to the risk of acquiring infections and fatal diseasessuch as AIDS, hepatitis, and other viral and prion diseases. In order toprevent that possible contamination a variety of expensive measures andtools are taken, but still only providing partial protection to themedical professional and the patient. A variety of materials are usedsuch as alcohol swabs, syringes, needles, sterile vials, gloves as wellas time and effort. Moreover, effort, time and money must be spent withthe disposal of biohazard materials such as the disposal of the sharpsand related biohazard material used to remove blood. These practicesnegatively affect the environment as those biohazard materials arenon-degradable and obviously made of non-recycled material.

In addition, these practices comprise a painful procedure withpuncturing the skin and putting the patient and nurse at risk forinfection, fatal diseases, contamination, and blood borne diseases.After all of this cumbersome, costly, time-consuming and hazardousprocedure, the vials with blood have to be transported by a humanattendant to the laboratory which is also costly. At the laboratory theblood is placed in other machines by a trained human operator with allof the risks and costs associated with the procedure of dealing withblood.

The conventional laboratory instruments then have to separate the bloodusing special and expensive machines and then materials are sent forfurther processing and analysis by a trained human operator. Subsequentto that the result is printed and sent to the patient and/or doctor,most frequently by regular mail. All of this process in laboratories isrisky, complex, cumbersome, and expensive; and this is only for onetest.

If a patient is admitted to a hospital, this very laborious andexpensive process could happen several times a day. Only one simpleblood test result can be over $100 dollars and this cost is easilyexplained by the labor and materials associated with the cost related tomanipulation of blood and protection against infections as describedabove. If four tests are needed over 24 hours, as may occur withadmitted patients, the cost then can increase to $400 dollars.

The world and in particular the United States face challenging healthcare costs with a grim picture of rapidly rising health careexpenditures with a rapid increase in the number and frequency oftesting. Today, the worldwide diabetic population alone is over 125million and is expected to reach 250 million by the year 2008. TheUnited States spent over $140 billion dollars on diabetes alone in 1998.More frequent control of blood glucose is known to prevent complicationsand would substantially reduce the costs of the disease.

According to the projections by the Health Care Financing Administrationof the United States Department of Health and Human Services, healthcare spending as a share of U.S. gross domestic product (GDP) isestimated to increase from 13 percent to potentially and amazingly closeto 20% of the United States GDP in the near future, reaching over $2trillion dollars a year, which clearly demonstrates how unwise healthcare spending can affect the overall economy of a nation.

The World Health Organization reported in 1995, the percentage of totalspending on health by various governments clearly indicating health carecosts as a serious global problem and important factor concerning theoverall utilization of public money. Public spending on health by theUnited States government was 47%, while United Kingdom was 84%, Francewas 81%, Japan was 78%, Canada was 71%, Italy was 70% and Mexico was56%.

Infrared spectroscopy is a technique based on the absorption of infraredradiation by substances with the identification of said substancesaccording to its unique molecular oscillatory pattern depicted asspecific resonance absorption peaks in the infrared region of theelectromagnetic spectrum. Each chemical substance absorbs infraredradiation in a uruque manner and has its own unique absorption spectradepending on its atomic and molecular arrangement and vibrational androtational oscillatory pattern. This unique absorption spectra allowseach chemical substance to basically have its own infrared spectrum,also referred as fingerprint or signature which can be used to identifyeach of such substances.

Radiation containing various infrared wavelengths is emitted at thesubstance or constituent to be measured, referred to herein as“substance of interest”, in order to identify and quantify saidsubstance according to its absorption spectra. The amount of absorptionof radiation is dependent upon the concentration of said chemicalsubstance being measured according to Beer-Lambert's Law.

When electromagnetic energy is emitted an enormous amount of interferingconstituents, besides the substance of interest, are also irradiatedsuch as skin, fat, wall of blood vessels, bone, cartilage, water, blood,hemoglobin, albumin, total protein, melanin, and various otherinterfering substances. Those interfering constituents and backgroundnoise such as changes in pressure and temperature of the sample,irradiated drastically reduce the accuracy and precision of themeasurements when using infrared spectroscopy. Those many constituentsand variables including the substance of interest form then anabsorption spectrum for each wavelength. The sum of the absorption foreach wavelength of radiation by all of the constituents and variablesgenerates the total absorption with said total absorption spectrum beingmeasured at two or more wavelengths of emission.

In order then to achieve the concentration of the substance of interest,a procedure must be performed to subtract the statistical absorptionspectra for each of the various intervening tissues and interferingconstituents, with the exception of the substance of interest beingmeasured. It is then assumed that all of the interfering constituentswere accounted for and completely eliminated and that the remainder isthe real spectra of the substance of interest. It has been verydifficult to prove this assumption in vivo as no devices or methods inthe prior art have yet shown to be clinically useful.

In the prior art the interfering constituents and variables introducesignificant source of errors which are particularly critical since thebackground noise as found in the prior art tremendously exceeds thesignal of the substance of interest which is found in minimalconcentrations relative to the whole sample irradiated. Furthermore, inthe prior art, the absorption of a solute such as glucose is very smallcompared to the other various interfering constituents which leads tomany statistical errors preventing the accurate statistical measurementof glucose concentration. A variety of other techniques using infrareddevices and methods have been described but all of them suffer from thesame limitation due to the great amount of interference and noise.

Other techniques based on comparison with a known reference signal aswith phase sensitive techniques have also the same limitations anddrawbacks due to the great number of interfering constituents andgeneration of only a very weak signal. The interfering constituents aresource of many artifacts, errors, and variability which leads toinadequate signal and severe reduction of the signal to noise ratio.Besides, calculation errors are common because of the many interferingsubstances and because the spectra of interfering constituents canoverlap with the spectra of the substance of the interest beingmeasured. If adequate signal to noise can be achieved, infraredspectroscopy should be able to provide a clinically useful device anddetermine the concentration of the substance of interest precisely andaccurately.

Attempts in the prior art using infrared spectroscopy for noninvasivemeasurement of chemical substances have failed to accurately andprecisely measure chemical substances such as for example glucose. Theprior art have used transcutaneous optical means, primarily using theskin non-invasively, to determine the concentration of chemicalsubstances. The prior art has also used invasive means with implant ofsensors inside blood vessels or around the blood vessels. The prior artused polarized light directed at the aqueous humor of the eye, which islocated inside the eye, in an attempt to measure glucose in said aqueoushumor. However, precise measurements are very difficult to achieveparticularly when there is substantial background noise and minimalconcentration of the substance of interest as it occurs in the aqueoushumor of the eye. Besides, polarized light techniques as used in theaqueous humor of the eye can only generate a very weak signal and thereis low concentration of the solute in the aqueous sample. Thecombination of those factors and presence of interfering constituentsand variables prevent accurate measurements to be achieved when usingthe aqueous humor of the eye.

The most frequent optical approaches in the prior art were based onmeasuring chemical substances using the skin. Other techniques includemeasuring substances in whole blood in the blood vessel (eithernon-invasively transcutaneously or invasively around or inside the bloodvessel). Yet attempts were made to measure substances present ininterstitial fluid with devices implanted under the skin. Attempts werealso made by the prior art using the oral mucosa and tongue.

Mucosal surfaces such as the oral mucosa are made to stand long wear andtear as occurs during mastication. If the oral mucosa or tongue liningwere thin with exposed vessels, one would easily bleed during chewing.Thus, those areas have rather thick lining and without plasma leakage.Furthermore these mucosal areas have no natural means for apposition ofa sensor such as a natural pocket formation.

Since there is still a low signal with an enormous amount of interferingconstituents, useful devices using the oral mucosal, tongue, and othermucosa such as genito-urinary and gastrointestinal have not beendeveloped. The prior art also attempted to measure glucose using farinfrared thermal emission from the body, but a clinically useful devicehas not been developed due to the presence of interfering elements andgreat thermal instability of the sample. Near infrared spectroscopy andfar-infrared techniques have been tried by the prior art as means tonon-invasively measure glucose, but accuracy and precision for clinicalapplication has not been achieved.

Therefore remains a need to provide a method and apparatus capable ofdelivering a higher signal to noise by reducing or eliminatinginterfering constituents, noise, and other variables, which willultimately provide the accuracy and precision needed for useful clinicalapplication.

SUMMARY OF THE INVENTION

In contrast to the various prior art devices, the apparatus of thepresent invention offers an entirely new approach for the measurement ofintraocular pressure and eye hydrodynamics. The apparatus offers asimple, accurate, low-cost and safe means of detecting and measuring theearliest of abnormal changes taking place in glaucoma, and provides amethod for the diagnosis of early forms of glaucoma before anyirreversible damage occurs. The apparatus of this invention provides afast, safe, virtually automatic, direct-reading, comfortable andaccurate measurement utilizing an easy-to-use, gentle, dependable andlow-cost device, which is suitable for home use.

Besides providing a novel method for a single measurement andself-measurement of intraocular pressure, the apparatus of the inventioncan also be used to measure outflow facility and ocular rigidity. Inorder to determine ocular rigidity it is necessary to measureintraocular pressure under two different conditions, either withdifferent weights on the tonometer or with the indentation tonometer andan applanation tonometer. Moreover, the device can perform applanationtonography which is unaffected by ocular rigidity because the amount ofdeformation of the cornea is so very small that very little is displacedwith very little change in pressure. Large variations in ocularrigidity, therefore, have little effect on applanation measurements.

According to the present invention, a system is provided for measuringintraocular pressure by applanation. The system includes a contactdevice for placement in contact with the cornea and an actuationapparatus for actuating the contact device so that a portion thereofprojects inwardly against the cornea to provide a predetermined amountof applanation. The contact device is easily sterilized for multipleuse, or alternatively, can be made inexpensively so as to render thecontact device disposable. The present invention, therefore, avoids thedanger present in many conventional devices of transmitting a variety ofsystemic and ocular diseases.

The system further includes a detecting arrangement for detecting whenthe predetermined amount of applanation of the cornea has been achievedand a calculation unit responsive to the detecting arrangement fordetermining intraocular pressure based on the amount of force thecontact device must apply against the cornea in order to achieve thepredetermined amount of applanation.

The contact device preferably includes a substantially rigid annularmember, a flexible membrane and a movable central piece. Thesubstantially rigid annular member includes an inner concave surfaceshaped to match an outer surface of the cornea and having a hole definedtherein. The subsannular member preferably has a maximum thickness atthe hole and a progressively decreasing thickness toward a periphery ofthe substantially rigid annular member.

The flexible membrane is preferably secured to the inner concave surfaceof the substantially rigid annular member. The flexible membrane iscoextensive with at least the hole in the annular member and includes atleast one transparent area. Preferably, the transparent area spans theentire flexible membrane, and the flexible membrane is coextensive withthe entire inner concave surface of the rigid annular member.

The movable central piece is slidably disposed within the hole andincludes a substantially flat inner side secured to the flexiblemembrane. A substantially cylindrical wall is defined circumferentiallyaround the hole by virtue of the increased thickness of the rigidannular member at the periphery of the hole. The movable central pieceis preferably slidably disposed against this wall in a piston-likemanner and has a thickness which matches the height of the cylindricalwall. In use, the substantially flat inner side flattens a portion ofthe cornea upon actuation of the movable central piece by the actuationapparatus.

Preferably, the actuation apparatus actuates the movable central pieceto cause sliding of the movable central piece in the piston-like mannertoward the cornea. In doing so, the movable central piece and a centralportion of the flexible membrane are caused to project inwardly againstthe cornea. A portion of the cornea is thereby flattened. Actuationcontinues until a predetermined amount of applanation is achieved.

Preferably, the movable central piece includes a magnetically responsiveelement arranged so as to slide along with the movable central piece inresponse to a magnetic field, and the actuation apparatus includes amechanism for applying a magnetic field thereto. The mechanism forapplying the magnetic field preferably includes a coil and circuitry forproducing an electrical current through the coil in a progressivelyincreasing manner. By progressively increasing the current, the magneticfield is progressively increased. The magnetic repulsion between theactuation apparatus and the movable central piece therefore increasesprogressively, and this, in turn, causes a progressively greater forceto be applied against the cornea until the predetermined amount ofapplanation is achieved.

Using known principles of physics, it is understood that the electricalcurrent passing through the coil will be proportional to the amount offorce applied by the movable central piece against the cornea via theflexible membrane. Since the amount of force required to achieve thepredetermined amount of applanation is proportional to intraocularpressure, the amount of current required to achieve the predeterminedamount of applanation will also be proportional to the intraocularpressure.

The calculation unit therefore preferably includes a memory for storinga current value indicative of the amount of current passing through thecoil when the predetermined amount of applanation is achieved and alsoincludes a conversion unit for converting the current value into anindication of intraocular pressure.

The magnetically responsive element is circumferentially surrounded by atransparent peripheral portion. The transparent peripheral portion isaligned with the transparent area and permits light to pass through thecontact device to the cornea and also permits light to reflect from thecornea back out of the contact device through the transparent peripheralportion.

The magnetically responsive element preferably comprises an annularmagnet having a central sight hole through which a patient is able tosee while the contact device is located on the patient's cornea. Thecentral sight hole is aligned with the transparent area of the flexiblemembrane.

A display is preferably provided for numerically displaying theintraocular pressure detected by the system. Alternatively, the displaycan be arranged so as to give indications of whether the intraocularpressure is within certain ranges.

Preferably, since different patients may have different sensitivities orreactions to the same intraocular pressure, the ranges are calibratedfor each patient by an-attending physician. This way, patients who aremore susceptible to consequences from increased intraocular pressure maybe alerted to seek medical attention at a pressure less than thepressure at which other less-susceptible patients are alerted to takethe same action.

The detecting arrangement preferably comprises an optical applanationdetection system. In addition, a sighting arrangement is preferablyprovided for indicating when the actuation apparatus and the detectingarrangement are properly aligned with the contact device. Preferably,the sighting arrangement includes the central sight hole in the movablecentral piece through which a patient is able to see while the device islocated on the patient's cornea. The central sight hole is aligned withthe transparent area, and the patient preferably achieves a generallyproper alignment by directing his vision through the central sight holetoward a target mark in the actuation apparatus.

The system also preferably includes an optical distance measuringmechanism for indicating whether the contact device is spaced at aproper axial distance from the actuation apparatus and the detectingarrangement. The optical distance measurement mechanism is preferablyused in conjunction with the sighting arrangement and preferablyprovides a visual indication of what corrective action should be takenwhenever an improper distance is detected.

The system also preferably includes an optical alignment mechanism forindicating whether the contact device is properly aligned with theactuation apparatus and the detecting arrangement. The optical alignmentmechanism preferably provides a visual indication of what correctiveaction should be taken whenever a misalignment is detected, and ispreferably used in conjunction with the sighting arrangement, so thatthe optical alignment mechanism merely provides indications of minoralignment corrections while the sighting arrangement provides anindication of major alignment corrections.

In order to compensate for deviations in corneal thickness, the systemof the present invention may also include an arrangement for multiplyingthe detected intraocular pressure by a coefficient (or gain) which isequal to one for corneas of normal thickness, less than one forunusually thick corneas, and a gain greater than one for unusually thincorneas.

Similar compensations can be made for corneal curvature, eye size,ocular rigidity, and the like. For levels of corneal curvature which arehigher than normal, the coefficient would be less than one. The samecoefficient would be greater than one for levels of corneal curvaturewhich are flatter than normal.

In the case of eye size compensation, larger than normal eyes wouldrequire a coefficient which is less than one, while smaller than normaleyes require a coefficient which is greater than one.

For patients with “stiffer” than normal ocular rigidities, thecoefficient is less than one, but for patients with softer ocularrigidities, the coefficient is greater than one.

The coefficient (or gain) may be manually selected for each patient, oralternatively, the gain may be selected automatically by connecting theapparatus of the present invention to a known pachymetry apparatus whencompensating for corneal thickness, a known keratometer whencompensating for corneal curvature, and/or a known biometer whencompensating for eye size.

The contact device and associated system of the present invention mayalso be used to detect intraocular pressure by indentation. Whenindentation techniques are used in measuring intraocular pressure, apredetermined force is applied against the cornea using an indentationdevice. Because of the force, the indentation device travels in towardthe cornea, indenting the cornea as it travels. The distance traveled bythe indentation device into the cornea in response to the predeterminedforce is known to be inversely proportional to intraocular pressure.Accordingly, there are various known tables which, for certain standardsizes of indentation devices and standard forces, correlate the distancetraveled and intraocular pressure.

Preferably, the movable central piece of the contact device alsofunctions as the indentation device. In addition, the circuit isswitched to operate in an indentation mode. When switched to theindentation mode, the current producing circuit supplies a predeterminedamount of current through the coil. The predetermined amount of currentcorresponds to the amount of current needed to produce one of theaforementioned standard forces.

In particular, the predetermined amount of current creates a magneticfield in the actuation apparatus. This magnetic field, in turn, causesthe movable central piece to push inwardly against the cornea via theflexible membrane. Once the predetermined amount of current has beenapplied and a standard force presses against the cornea, it is necessaryto determine how far the movable central piece moved into the cornea.

Accordingly, when measurement of intraocular pressure by indentation isdesired, the system of the present invention further includes a distancedetection arrangement for detecting a distance traveled by the movablecentral piece, and a computation portion in the calculation unit fordetermining intraocular pressure based on the distance traveled by themovable central piece in applying the predetermined amount of force.

Preferably, the computation portion is responsive to the currentproducing circuitry so that, once the predetermined amount of force isapplied, an output voltage from the distance detection arrangement isreceived by the computation portion. The computation portion then, basedon the displacement associated with the particular output voltage,determines intraocular pressure.

In addition, the present invention includes alternative embodiments, aswill be described hereinafter, for performing indentation-relatedmeasurements of the eye. Clearly, therefore, the present invention isnot limited to the aforementioned exemplary indentation device.

The aforementioned indentation device of the present invention may alsobe utilized to non-invasively measure hydrodynamics of an eye includingoutflow facility. The method of the present invention preferablycomprises several steps including the following:

According to a first step, an indentation device is placed in contactwith the cornea. Preferably, the indentation device comprises thecontact device of the present invention.

Next, at least one movable portion of the indentation device is moved intoward the cornea using a first predetermined amount of force to achieveindentation of the cornea. An intraocular pressure is then determinedbased on a first distance traveled toward the cornea by the movableportion of the indentation device during application of the firstpredetermined amount of force. Preferably, the intraocular pressure isdetermined using the aforementioned system for determining intraocularpressure by indentation.

Next, the movable portion of the indentation device is rapidlyreciprocated in toward the cornea and away from the cornea at a firstpredetermined frequency and using a second predetermined amount of forceduring movement toward the cornea to thereby force intraocular fluid outfrom the eye. The second predetermined amount of force is preferablyequal to or more than the first predetermined amount of force. It isunderstood, however, that the second predetermined amount of force maybe less than the first predetermined amount of force.

The movable portion is then moved in toward the cornea using a thirdpredetermined amount of force to again achieve indentation of thecornea. A second intraocular pressure is then determined based on asecond distance traveled toward the cornea by the movable portion of theindentation device during application of the third predetermined amountof force. Since intraocular pressure decreases as a result of forcingintraocular fluid out of the eye during the rapid reciprocation of themovable portion, it is generally understood that, unless the eye is sodefective that no fluid flows out therefrom, the second intraocularpressure will be less than the first intraocular pressure. Thisreduction in intraocular pressure is indicative of outflow facility.

Next, the movable portion of the indentation device is again rapidlyreciprocated in toward the cornea and away from the cornea, but at asecond predetermined frequency and using a fourth predetermined amountof force during movement toward the cornea. The fourth predeterminedamount of force is preferably equal to or greater than the secondpredetermined amount of force; however, it is understood that the fourthpredetermined amount of force maybe less than the second predeterminedamount of force. Additional intraocular fluid is thereby forced out fromthe eye.

The movable portion is subsequently moved in toward the cornea using afifth predetermined amount of force to again achieve indentation of thecornea. Thereafter, a third intraocular pressure is determined based ona third distance traveled toward the cornea by the movable portion ofthe indentation device during application of the fifth predeterminedamount of force.

The differences are then preferably calculated between the first,second, and third distances, which differences are indicative of thevolume of intraocular fluid which left the eye and therefore are alsoindicative of the outflow facility. It is understood that the differencebetween the first and last distances may be used, and in this regard, itis not necessary to use the differences between all three distances. Infact, the difference between any two of the distances will suffice.

Although the relationship between the outflow facility and the detecteddifferences varies when the various parameters of the method and thedimensions of the indentation device change, the relationship for givenparameters and dimensions can be easily determined by known experimentaltechniques and/or using known Friedenwald Tables.

Preferably, the method further comprises the steps of plotting thedifferences between the first, second, and third distance to a create agraph of the differences and comparing the resulting graph ofdifferences to that of a normal eye to determine if any irregularitiesin outflow facility are present.

Additionally, the present invention relates to the utilization of acontact device placed on the front part of the eye in order to detectphysical and chemical parameters of the body as well as the non-invasivedelivery of compounds according to these physical and chemicalparameters, with signals preferably being transmitted continuously aselectromagnetic waves, radio waves, infrared and the like. One of theparameters to be detected includes non-invasive blood analysis utilizingchemical changes and chemical products that are found in the front partof the eye and in the tear film. The non-invasive blood analysis andother measurements are done using the system of my co-pending priorapplication, characterized as an intelligent contact lens system.

The word lens is used here to define an eyepiece which fits inside theeye regardless of the presence of optical properties for correction ofimperfect vision. The word intelligent used here defines a lens capableof signal-detection and/or signal-transmission and/or signal-receptionand/or signal-emission and/or signal-processing and analysis as well asthe ability to alter physical, chemical, and or biological variables.When the device is placed in other parts of the body other than the eye,it is referred to as a contact device or intelligent contact device(ICD).

An alternative embodiment of the present invention will now bedescribed. The apparatus and method is based on a different and novelconcept originated by the inventor in which a transensor mounted in thecontact device laying on the cornea or the surface of the eye is capableof evaluating and measuring physical and chemical parameters in the eyeincluding non-invasive blood analysis. The alternative embodimentpreferably utilizes a transensor mounted in the contact device which ispreferably laying in contact with the cornea and is preferably activatedby the process of eye lid motion and/or closure of the eye lid. Thesystem preferably utilizes eye lid motion and/or closure of the eye lidto activate a microminiature radio frequency sensitive transensormounted in the contact device. The signal can be communicated by cable,but is preferably actively or passively radio telemetered to anexternally placed receiver. The signal can then be processed, analyzedand stored.

This eye lid force and motion toward the surface of the eye is alsocapable to create the deformation of any transensor/electrodes mountedon the contact device. During blinking, the eye lids are in full contactwith the contact device and the transensor's surface is in contact withthe cornea/tear film and/or inner surface of the eye lid and/or bloodvessels on the surface of the conjunctiva. It is understood that thetransensor used for non-invasive blood analysis is continuouslyactivated when placed on the eye and do not need closure of the eyelidfor activation. It is understood that after a certain amount of time thecontact device will adhere to tissues in the conjunctiva optimizing flowof tissue fluid to sensors for measurement of blood components.

The present invention includes apparatus and methods that utilizes acontact device laying on the surface of the eye called intelligentcontact lens (ICL) which provides means for transmitting physiologic,physical, and chemical information from one location as for instanceliving tissue on the surface of the eye to another remote locationaccurately and faithfully reproducing the event at the receiver. In myprior copending application, the whole mechanism by which the eye lidactivate transensors is described and a microminiature passivepressure-sensitive radio frequency transducer is disclosed tocontinuously measure intraocular pressure and eye fluid outflow facilitywith both open and closed eyes.

The present invention provides a new method and apparatus to detectphysical and chemical parameters of the body and the eye utilizing acontact device placed on the eye with signals being transmittedcontinuously as electromagnetic waves, radio waves, sound waves,infrared and the like. Several parameters can be detected with theinvention including a complete non-invasive analysis of bloodcomponents, measurement of systemic and ocular blood flow, measurementof heart rate and respiratory rate, tracking operations, detection ofovulation, detection of radiation and drug effects, diagnosis of ocularand systemic disorders and the like. The invention also provides a newmethod and apparatus for somnolence awareness, activation of devices bydisabled individuals, a new drug delivery system and new therapy forocular and neurologic disorders, and treatment of cancer in the eye orother parts of the body, and an evaluation system for the overall healthstatus of an individual. The device of the present invention quantifiesnon-invasively the amount of the different chemical components in theblood using a contact device with suitable electrodes and membraneslaying on the surface of the eye and in direct contact with the tearfilm or surface of the eye, with the data being preferably transmittedutilizing radio waves, but alternatively sound waves, light waves, wire,or telephone lines can be used for transmission.

The system comprises a contact device in which a microminiature radiofrequency transensor, actively or passively activated, such asendoradiosondes, are mounted in the contact device which in turn ispreferably placed on the surface of the eye. A preferred method involvessmall passive radio telemetric transducers capable of detecting chemicalcompounds, electrolytes, glucose, cholesterol, and the like on thesurface of the eye. Besides using passive radio transmission orcommunication by cable, active radio transmission with activetransmitters contained a microminiature battery mounted in the contactdevice can also be used.

Several means and transensors can be mounted in the contact device andused to acquire the signal. Active radio transmitters using transensorswhich are energized by batteries or using cells that can be recharged inthe eye by an external oscillator, and active transmitters which can bepowered from a biologic source can also be used and mounted in thecontact device. The preferred method to acquire the signal involvespassive radio frequency transensors, which contain no power source. Theyact from energy supplied to it from an external source. The transensortransmits signals to remote locations using different frequenciesindicative of the levels of chemical and physical parameters. Theseintraocular recordings can then be transmitted to remote extra ocularradio frequency monitor stations with the signal sent to a receiver foramplification and analysis. Ultrasonic micro-circuits can also bemounted in the contact device and modulated by sensors which are capableof detecting chemical and physical changes in the eye. The signal may betransmitted using modulated sound signals particularly under watersbecause sound is less attenuated by water than are radio waves. Thesonic resonators can be made responsive to changes in temperature andvoltage which correlate to the presence and level of molecules such asglucose and ions in the tear film.

Ocular and systemic disorders may cause a change in the pH, osmolarity,and temperature of the tear film or surface of the eye as well as changein the tear film concentration of substances such as acid-lactic,glucose, lipids, hormones, gases, enzymes, inflammatory mediators,plasmin, albumin, lactoferrin, creatinin, proteins and so on. Besidespressure, outflow facility, and other physical characteristics of theeye, the apparatus of the invention is also capable of measuring theabove physiologic parameters in the eye and tear film usingtransensor/electrodes mounted in the contact device. These changes inpressure, temperature, pH, oxygen level, osmolality, concentration ofchemicals, and so on can be monitored with the eyes opened or closed orduring blinking. In some instance such as with the evaluation of pH,metabolites, and oxygen concentration, the device does not neednecessarily eye lid motion because just the contact with the transensormounted in the contact device is enough to activate thetransensor/electrodes.

The presence of various chemical elements, gases, electrolytes, and pHof the tear film and the surface of the eye can be determined by the useof suitable electrodes and a suitable permeable membrane. Theseelectrodes, preferably microelectrodes, can be sensitized by severalreacting chemicals which are in the tear film or the surface of the eye,in the surface of the cornea or preferably the vascularized areas in thesurface of the eye. The different chemicals and substances diffusethrough suitable permeable membranes sensitizing suitable sensors.Electrodes and sensors to measure the above compounds are available fromseveral manufacturers.

The level of oxygen can be measured in the eye with the contact device,and in this case just the placement of the contact device would beenough to activate the system and eye lid motion and/or closure of theeye lid may not be necessary for its operation. Reversible mechanicalexpansion methods, photometric, or electrochemical methods andelectrodes can be mounted in the device and used to detect acidity andgases concentration. Oxygen gas can also be evaluated according to itsmagnetic properties or be analyzed by micro-polarographic sensorsmounted in the contact device. Moreover, the same sensor can measuredifferent gases by changing the cathode potential. Carbon dioxide,carbon monoxide, and other gases can also be detected in a similarfashion.

Microminiature glass electrodes mounted in the contact device can beused to detect divalent cations such as calcium, as well as sodium andpotassium ion and pH. Chloride-ion detector can be used to detect thesalt concentration in the tear film and the surface of the eye. Thesignal can be radio transmitted to a receiver and then to a screen forcontinuous recording and monitoring. This allows for the continuousnon-invasive measurement of electrolytes, chemicals and pH in the bodyand can be very useful in the intensive care unit setting.

A similar transensor can also be placed not in the eye, but in contactwith other mucosas and secretions in the body, such as the oral mucosa,and the concentration of chemicals measured in the saliva or even sweator any other body secretion with signals being transmitted to a remotelocation via ultrasonic or radio waves and the like. However, due to thehigh concentration of enzymes in the saliva and in other secretion, theelectrodes and electronics could be detrimentally affected which wouldimpact accuracy. Furthermore, there is a weak correlation betweenconcentration of chemicals in body secretions and blood.

The tear fluid proves to be the most reliable location and indicator ofthe concentration of chemicals, both organic and inorganic, but otherareas of the dye can be utilized to measure the concentration ofchemicals. The tear fluid and surface of the eye are the preferredlocation for these measurements because the tear film and aqueous humor(which can be transmitted through the intact cornea) can be consideredan ultrafiltrate of the plasma.

The apparatus and method of the present invention allows the leasttraumatic way of measuring chemicals in the body without the need ofneedle stick and the manipulation of blood. For instance, this may beparticularly important as compared to drawing blood from infants becausethe results provided by the drawn blood sample may not be accurate.There is a dramatic change in oxygen and carbon dioxide levels becauseof crying, breath holding and even apnea spells that occur during theprocess of restraining the baby and drawing blood. Naturally, theability to painlessly measure blood components without puncturing thevessel is beneficial also to any adult who needs a blood work-up,patients with diabetes who need to check their glucose level on a dailybasis, and health care workers who would be less exposed to severediseases such as AIDS and hepatitis when manipulating blood. Patients inintensive care units would benefit by having a continuous painlessmonitoring of electrolytes, gases, and so on by non-invasive means usingthe intelligent contact lens system. Moreover, there is no time wastedtransporting the blood sample to the laboratory, the data is availableimmediately and continuously.

The different amounts of eye fluid encountered in the eye can be easilyquantified and the concentration of substances calibrated according tothe amount of fluid in the eye. The relationship between theconcentration of chemical substances and molecules in the blood and theamount of said chemical substances in the tear fluid can be describedmathematically and programmed in a computer since the tear film can beconsidered an ultrafiltrate of the plasma and diffusion of chemicalsfrom capillaries on the surface of the eye have a direct correspondenceto the concentration in the blood stream.

Furthermore, when the eyes are closed there is an equilibrium betweenthe aqueous humor and the tear fluid allowing measurement of glucose ina steady state and since the device can send signals through theintervening eyelid, the glucose can be continuously monitored in thissteady state condition. Optical sensors mounted in the contact devicecan evaluate oxygen and other gases in tissues and can be used to detectthe concentration of compounds in the surface of the eye and thus notnecessarily have to use the tear film to measure the concentration ofsaid substances. In all instances, the signals can be preferably radiotransmitted to a monitoring station. Optical, acoustic, electromagnetic,micro-electromechanical systems and the like can be mounted in thecontact device and allow the measurement of blood components in the tearfilm, surface of the eye, conjunctival vessels, aqueous humor, vitreous,and other intraocular and extraocular structures.

Any substance present in the blood can be analyzed in this way since asmentioned the fluid measured is a filtrate of the blood. Rapidlyresponding microelectrodes with very thin membranes can be used tomeasure these substances providing a continuous evaluation. For example,inhaled anesthetics become blood gases and during an experiment theconcentration of anesthetics present in the blood could be evaluated inthe eye fluid. Anesthetics such as nitrous oxide and halothane can bereduced electrochemically at noble metal electrodes and the electrodescan be mounted in the contact device. Oxygen sensors can also used tomeasure the oxygen of the sample tear film. Measurement of oxygen andanesthetics in the blood has been performed and correlated well with theamount of the substances in the eye fluid with levels in the tear fluidwithin 85-95% of blood levels. As can be seen, any substances not onlythe ones naturally present, but also artificially inserted in the bloodcan be potentially measured in the eye fluid. A correction factor may beused to account for the differences between eye fluid and blood. Inaddition, the non-invasive measurement and detection by the ICL ofexogenous substances is a useful tool to law enforcement agents forrapidly testing and detecting drugs and alcohol.

The evaluation of systemic and ocular hemodynamics can be performed withsuitable sensors mounted in the contact device. The measurements ofblood pulsations in the eye can be done through electrical means byevaluating changes in impedance. Blood flow rate can be evaluated byseveral techniques including but not limited to ultrasonic andelectromagnetic meters and the signals then radio transmitted to anexternally placed device. For the measurement of blood flow, the contactdevice is preferably placed in contact with the conjunctiva, eitherbulbar orpalpebral, due to the fact that the cornea is normally anavascular structure. Changing in the viscosity of blood can also beevaluated from a change in damping on a vibrating quartz micro-crystalmounted in the contact device.

The apparatus of the invention may also measure dimension such as thethickness of the retina, the amount of cupping in the optic nerve head,and so on by having a microminiature ultrasound device mounted in thecontact device and placed on the surface of the eye. Ultra sonictimer/exciter integrated circuits used in both continuous wave andpulsed bidirectional Doppler blood flowmeters are in the order fewmillimeters in length and can be mounted in the apparatus of theinvention.

For the measurement of hemodynamics, the contact device shouldpreferably be placed in contact with the conjunctiva and on top of ablood vessel. Doppler blood microflowmeters are available and continuouswave (CW) and pulsed Doppler instruments can be mounted in the contactdevice to evaluate blood flow and the signal radio transmitted to anexternal receiver. The Doppler flowmeters may also use ultrasonictransducers and these systems can be fabricated in miniature electronicpackages and mounted in the contact device with signals transmitted to aremote receiver.

Illumination of vessels, through the pupil, in the back of the eye canbe used to evaluate blood flow velocity and volume or amount of cupping(recess) in the optic nerve head. For this use the contact device hasone or more light sources located near the center and positioned in away to reach the vessels that exit the optic nerve head, which are thevessels of largest diameter on the surface of the retina. A precisealignment of beam is possible because the optic nerve head is situatedat a constant angle from the visual axis. Sensors can be also positionedon the opposite side of the illumination source and the reflected beamreaching the sensor. Multioptical filters can be housed in the contactdevice with the light signal converted to voltage according to the angleof incidence of reflected light.

Moreover, the intracranial pressure could be indirectly estimated by theevaluation of changes and swelling in the retina and optic nerve headthat occurs in these structures due to the increased intracerebralpressure. Fiber optics from an external light source or light sourcesbuilt in the contact device emit a beam of plane-polarized light fromone side at three o=clock position with the beam entering through thecornea and passing through the aqueous humor and exiting at the nineo=clock position to reach a photodetector. Since glucose can rotate theplane of polarization, the amount of optical rotation would becompared-to a second reference beam projected in the same manner butwith a wavelength that it is insensitive to glucose with the differencebeing indicative of the amount of glucose present in the aqueous humorwhich can be correlated to plasma glucose by using a correction factor.

A dielectric constant of several thousand can be seen in blood and amicrominiature detector placed in the contact device can identify thepresence of blood in the surface of the cornea. Moreover, blood causesthe decomposition of hydrogen peroxide which promotes an exothermicreaction that can be sensed with a temperature-sensitive transensor.Small lamps energized by an external radio-frequency field can bemounted in the contact device and photometric blood detectors can beused to evaluate the presence of blood and early detection ofneovascularization in different parts of the eye and the body.

A microminiature microphone can be mounted in the contact device andsounds from the heart, respiration, flow, vocal and the environment canbe sensed and transmitted to a receiver. In cases of abnormal heartrhythm, the receiver would be carried by the individual and will havemeans to alert the individual through an alarm circuit either by lightor sound signals of the abnormality present. Changes in heart beat canbe detected and the patient alerted to take appropriate action.

The contact device can also have elements which produce and radiaterecognizable signals and this procedure could be used to locate andtrack individuals, particularly in military operations. A permanentmagnet can also be mounted in the contact device and used for trackingas described above.

Life threatening injuries causing change in heart rhythm and respirationcan be detected since the cornea pulsates according to heartbeat. Motionsensitive microminiature radio frequency transensors can be mounted inthe contact device and signals indicative of injuries can be radiotransmitted to a remote station particularly for monitoring duringcombat in military operations.

In rocket or military operations or in variable g situations, theparameters above can be measured and monitored by utilizing materials inthe transensor such as light aluminum which are less sensitive togravitational and magnetic fields. Infrared emitters can be mounted inthe contact device and used to activate distinct photodetectors byocular commands such as in military operations where fast action isneeded without utilizing hand movement.

Spinal cord injuries have lead thousands of individuals to completeconfinement in a wheel chair. The most unfortunate situation occurs withquadriplegic individuals who virtually only have useful movement oftheir mouth and eyes. The apparatus of the invention allows theseindividuals to use their remaining movement ability to become moreindependent and capable of indirect manipulation of a variety ofhardware. In this embodiment, the ICL uses blinking or closure of theeyes to activate remotely placed receptor photodiodes through theactivation of an LED drive coupled with a pressure sensor.

The quadriplegic patient focuses on a receptor photo diode and closestheir eyes for 5 seconds, for example. The pressure exerted by theeyelid is sensed by the pressure sensor which is coupled with a timingchip. If the ICL is calibrated for 5 sec, after this amount of timeelapses with eyes closed, the LED drive activates the LED which emitsinfrared light though the intervening eyelid tissue reaching suitablereceptor photodiodes or suitable optical receivers connected to a poweron or off circuit. This allows quadriplegics to turn on, turn off, ormanipulate a variety of devices using eye motion. It is understood thatan alternative embodiment can use more complex integrated circuitsconnected by fine wires to the ICL placed on the eye in order to performmore advanced functions such as using LED=s of different wavelengths.

Another embodiment according to the present invention includes asomnolence alert device using eye motion to detect premonitory signs ofsomnolence related to a physiologic condition called Bell phenomena inwhich the eye ball moves up and slightly outwards when the eyes areclosed. Whenever an individual starts to fall asleep, the eye lid comesdown and the eyes will move up.

A motion or pressure sensor mounted in the superior edge of the ICL willcause, with the Bell phenomena, a movement of the contact deviceupwards. This movement of the eye would position the pressure sensitivesensor mounted in the contact device against the superior cul-de-sac andthe pressure created will activate the sensor which modulates a radiotransmitter. The increase in pressure can be timed and if the pressureremains increased for a certain length of time indicating closed eyes,an alarm circuit is activated. The signal would then be transmitted to areceiver coupled with an alarm circuit and speaker creating a soundsignal to alert the individual at the initial indication of fallingasleep. Alternatively, the pressure sensor can be positioned on theinferior edge Of the ICL and the lack of pressure in the inferiorlyplaced sensor would activate the circuit as described above.

It is also understood that other means to activate a circuit in thecontact device such as closing an electric circuit due to motion orpressure shift in the contact device which remotely activate an alarmcan be used as a somnolence awareness device. It is also understood thatany contact device with sensing elements capable of sensing Bellphenomena can be used as a somnolence awareness device. This system,device and method are an important tool in diminishing car accidents andmachinery accidents by individuals who fall sleep while operatingmachinery and vehicles.

If signs of injury in the eye are detected, such as increasedintraocular pressure (IOP), the system can be used to release medicationwhich is placed in the cul-de-sac in the lower eye lid as a reservoir orpreferably the contact lens device acts as a reservoir for medications.A permeable membrane, small fenestrations or a valve like system withmicro-gates, or micro-electronic systems housed in the contact devicestructure could be electrically, magnetically, electronically, oroptically activated and the medication stored in the contact devicereleased. The intelligent lenses can thus be used as non-invasive drugdelivery systems. Chemical composition of the tear film, such as thelevel of electrolytes or glucose, so that can be sensed and signalsradio transmitted to drug delivery pumps carried by the patient so thatmedications can be automatically delivered before symptoms occur.

A part of the contact transducer can also be released, for instance ifthe amount of enzymes increases. The release of part of the contactdevice could be a reservoir of lubricant fluid which will automaticallybe released covering the eye and protecting it against the insultingelement. Any drugs could be automatically released in a similar fashionor through transmission of signal to the device.

An alternative embodiment includes the contact device which has acompartment filled with chemical substances or drugs connected to athread which keeps the compartments sealed. Changes in chemicals in thetear fluid or the surface of the eye promote voltage increases whichturns on a heater in the circuit which melts the thread allowingdischarge of the drug housed in the compartment such as insulin if thereis an increase in the levels of glucose detected by the glucose sensor.

To measure temperature, the same method and apparatus applies, but inthis case the transmitter is comprised of a temperature-sensitiveelement. A microminiature temperature-sensitive radio frequencytransensor, such as thermistor sensor, is mounted in the contact devicewhich in turn is placed on the eye with signals preferably radiotransmitted to a remote station. Changes in temperature and body heatcorrelate with ovulation and the thermistor can be mounted in thecontact device with signals telemetered to a remote station indicatingoptimum time for conception.

The detection and transmission to remote stations of changes intemperature can be used on animals for breeding purposes. Theintelligent contact lens can be placed on the eye of said animals andcontinuous monitoring of ovulation achieved. When this embodiment isused, the contact device with the thermistor is positioned so that itlodges against the palpebral conjunctiva to measure the temperature atthe palpebral conjunctiva. Monitoring the conjunctiva offers theadvantages of an accessible tissue free of keratin, a capillary levelclose to the surface, and a tissue layer vascularized by the samearterial circulation as the brain. When the lids are closed, the thermalenvironment of the cornea is exclusively internal with passiveprevention of heat loss during a blink and a more active heat transferduring the actual blink.

In carotid artery disease due to impaired blood supply to the eye, theeye has a lower temperature than that of the fellow eye which indicatesa decreased blood supply. If a temperature difference greater thannormal exists between the right and left eye, then there is an asymmetryin blood supply. Thus, this embodiment can provide information relatedto carotid and central nervous system vascular disorders. Furthermore,this embodiment can provide information concerning intraocular tumorssuch as melanoma. The area over a malignant melanoma has an increase intemperature and the eye harboring the malignant melanoma would have ahigher temperature than that of the fellow eye. In this embodiment thethermistor is combined with a radio transmitter emitting an audio signalfrequency proportional to the temperature.

Radiation sensitive endoradiosondes are known and can be used in thecontact device to measure the amount of radiation and the presence ofradioactive corpuscules in the tear film or in front of the eye whichcorrelates to its presence in the body. The amount of hydration andhumidity of the eye can be sensed with an electrical discharge andvariable resistance moisture sensor mounted in the contact device.Motion and deceleration can be detected by a mounted accelerometer inthe contact device. Voltages accompanying the function of the eye,brain, and muscles can be detected by suitable electrodes mounted in thedevice and can be used to modulate the frequency of the transmitter. Inthe case of transmission of muscle potentials, the contact device isplaced not on the cornea, but next to the extraocular muscle to beevaluated and the signals remotely transmitted. A fixed frequencytransmitter can be mounted in the contact device and used as a trackingdevice which utilizes a satellite tracking system by noting thefrequency received from the fixed frequency transmitter to a passingsatellite.

A surface electrode mounted in the contact device may be activated byoptical or electromagnetic means in order to increase the temperature ofthe eye. This increase in temperature causes a dilation of the capillarybed and can be used in situations in which there is hypoxia (decreasedoxygenation) in the eye. The concept and apparatus called heatstimulation transmission device (HSTD) is based upon my experiments andin the fact that the eye has one of largest blood supply per gram oftissue in the body and has the unique ability to be overpefused whenthere is an increase in temperature. The blood flow to the eye can thusbe increased with a consequent increase in the amount of oxygen. Theelectrode can be placed in any part of the eye, inside or outside, butis preferably placed on the most posterior part of the eye. The radiofrequency activated heating elements can be externally placed orsurgically implanted according to the area in need of increase in theamount of oxygen in the eye. It is understood that the same heatingelements could be placed or implanted in other parts of the body.Naturally, means that promote an increase in temperature of the eyewithout using electrodes can be used as long as the increase intemperature is sufficient to increase blood flow without promoting anyinjury.

The amount of increase varies from individual to individual andaccording to the status of the vascular bed of the eye. The increase intemperature of blood in the eye raises its oxygen level about 6% pereach one degree Celsius of increase in temperature allowing precisequantification of the increase in oxygen by using a thermistor whichsimultaneously indicates temperature, or alternatively an oxygen sensorcan be used in association with the heating element and actual amount ofincrease in oxygen detected.

This increase in blood flow can be timed to occur at predetermined hoursin the case of chronic hypoxia such as in diabetes, retinaldegenerations, and even glaucoma. These devices can be externally placedor surgically implanted in the eye or other parts of the body accordingto the application needed.

Another embodiment is called over heating transmission device (OHTD) andrelates to a new method and apparatus for the treatment of-tumors in theeye or any other part of the body by using surgically implanted orexternally placed surface electrodes next to a tumor with the electrodesbeing activated by optical or electromagnetic means in order to increasethe temperature of the cancerous tissue until excessive localized heatdestroys the tumor cells. These electrodes can be packaged with athermistor and the increase in temperature sensed by the thermistor withthe signal transmitted to a remote station in order to evaluate thedegree of temperature increase.

Another embodiment concerning therapy of eye and systemic disordersinclude a neuro-stimulation transmission device (NSTD) which relates toa system in which radio activated micro-photodiodes or/andmicro-electric circuits and electrodes are surgically implanted orexternally placed on the eye or other parts of the body such as thebrain and used to electrically stimulate non-functioning neural ordegenerated neural tissue in order to treat patients with retinaldegeneration, glaucoma, stroke, and the like. Multiple electrodes canbe-used in the contact device, placed on the eye or in the brain forelectrical stimulation of surrounding tissues with consequentregeneration of signal transmission by axonal and neural cells andregeneration of action potential with voltage signals being transmittedto a remote station.

Radio and sonic transensors to measure pressure, electrical changes,dimensions, acceleration, flow, temperature, bioelectric activity andother important physiologic parameters and power switches to externallycontrol the system have been developed and are suitable systems to beused in the apparatus of the invention. The sensors can be automaticallyturned on and off with power switches externally controlling theintelligent contact lens system. The use of integrated circuits andadvances occurring in transducer, power source, and signal processingtechnology allow for extreme miniaturization of the components whichpermits several sensors to be mounted in one contact device. Forinstance, typical resolutions of integrated circuits are in the order ofa few microns and very high density circuit realization can be achieved.Radio frequency and ultrasonic microcircuits are available and can beused and mounted in the contact device. A number of different ultrasonicand pressure transducers are also available and can be used and mountedin the contact device.

Technologic advances will occur which allow full and novel applicationsof the apparatus of the invention such as measuring enzymatic reactionsand DNA changes that occur in the tear fluid or surface of the eye, thusallowing an early diagnosis of disorders such as cancer and heartdiseases. HIV virus is present in tears and AIDS could be detected withthe contact device by sensors coated with antibodies against the viruswhich would create a photochemical reaction with appearance ofcolorimetric reaction and potential shift in the contact device withsubsequent change in voltage or temperature that can be transmitted to amonitoring station.

A variety of other pathogens could be identified in a similar fashion.These signals can be radio transmitted to a remote station for furthersignal processing and analysis. In the case of the appearance offluorescent light, the outcome could be observed on a patient=s eyesimply by illuminating the eye with light going through a cobalt filterand in this embodiment the intelligent contact lens does not need tonecessarily have signals transmitted to a station.

The system further comprises a contact device in which a microminiaturegas-sensitive, such as oxygen-sensitive, radio frequency transensor ismounted in the contact device which in turn is placed on the corneaand/or surface of the eye. The system also comprises a contact device inwhich a microminiature blood velocity-sensitive radio frequencytransensor is mounted in the contact device which in turn is placed onthe conjunctiva and is preferably activated by eye lid motion and/orclosure of the eye lid. The system also comprises a contact device inwhich a radio frequency transensor capable of measuring the negativeresistance of nerve fibers is mounted in the contact device which inturn is preferably placed on the cornea and/or surface of the eye. Bymeasuring the electrical resistance, the effects of microorganisms,drugs, poisons and anesthetics can be evaluated. The system alsocomprises a contact device in which a microminiature radiation-sensitiveradio frequency transensor is mounted in the contact device which inturn is preferably placed on the cornea.

The contact device preferably includes a rigid or flexible annularmember in which a transensor is mounted in the device. The transensor ispositioned in a way to allow passage of light through the visual axis.The annular member preferably includes an inner concave surface shapedto match an outer surface of the eye and having one or more holesdefined therein in which transensors are mounted. It is understood thatthe contact device conforms in general shape to the surface of the eyewith its dimensions and size chosen to achieve optimal comfort level andtolerance. It is also understood that the curvature and shape of thecontact device is chosen to intimately and accurately fit the contactdevice to the surface of the eye for optimization of sensor function.The surface of the contact device can be porous or microporous as wellas with mircro-protuberances on the surface. It is also understood thatfenestrations can be made in the contact device in order to allow betteroxygenation of the cornea when the device is worn for a long period oftime. It is also understood that the shape of the contact device mayinclude a ring-like or band-like shape without any material covering thecornea. It is also understood that the contact device may have a basedown prism or truncated edge for better centration. It is alsounderstood that the contact device preferably has a myoflange or a minuscarrier when a conventional contact lens configuration is used. It isalso understood that an eliptical, half moon shape or the like can beused for placement under the eyelid. It is understood that the contactdevice can be made with soft of hard material according to theapplication needed. It is also understood that an oversized cornealscleral lens covering the whole anterior surface of the eye can be usedas well as hourglass shaped lenses and the like. It is understood alsothat the external surface of the contact device can be made withpolymers which increases adherence to tissues or coating which increasesfriction and adherence to tissues in order to optimize fluid passage tosensors when measuring chemical components. It is understood that thedifferent embodiments which are used under the eyelids are shaped to fitbeneath the upper and/or eyelids as well as to fit the upper or lowercul-de-sac.

The transensor may consist of a passive or active radio frequencyemitter, or a miniature sonic resonator, and the like which can becoupled with miniature microprocessor mounted in the contact device. Thetransensors mounted in the contact device can be remotely driven byultrasonic waves or alternatively remotely powered by electromagneticwaves or by incident light. They can also be powered by microminiaturelow voltage batteries which are inserted into the contact device.

As mentioned, preferably the data is transmitted utilizing radio waves,sound waves, light waves, by wire, or by telephone lines. The describedtechniques can be easily extrapolated to other transmission systems. Thetransmitter mounted in the contact device can use the transmission linksto interconnect to remote monitoring sites. The changes in voltage orvoltage level are proportional to the values of the biological variablesand this amplified physiologic data signal from the transducers may befrequency modulated and then transmitted to a remote external receptionunit which demodulates and reconstitutes the transmitted frequencymodulated data signal preferably followed by a low pass filter with theregeneration of an analog data signal with subsequent tracing on astrip-chart recorder.

The apparatus of the invention can also utilize a retransmiter in orderto minimize electronic components and size of the circuit housed in thecontact device. The signal from a weak transmitter can be retransmittedto a greater distance by an external booster transmitter carried by thesubject or placed nearby. It is understood that a variety of noisedestruction methods can be used in the apparatus of the invention.

Since the apparatus of the invention utilizes externally placed elementson the surface of the eye that can be easily retrieved, there is notissue damage due to long term implantation and if drift occurs it ispossible to recalibrate the device. There are a variety of formats thatcan be used in the apparatus of the invention in which biologic data canbe encoded and transmitted. The type of format for a given applicationis done according to power requirement, circuit complexity, dimensionsand the type of biologic data to be transmitted. The general layout ofthe apparatus preferably includes an information source with a varietyof biological variables, a transducer, a multiplexer, a transmitter, atransmission path and a transmission medium through which the data istransmitted preferably as a coded and modulated signal.

The apparatus of the invention preferably includes a receiver whichreceives the coded and modulated signal, an amplifier and low passfilter, a demultiplexer, a data processing device, a display andrecording equipment, and preferably an information receiver, a CPU, amodem, and telephone connection. A microprocessor unit containing anautodialing telephone modem which automatically transmits the data overthe public telephone network to a hospital based computer system can beused. It is understood that the system may accept digitally codedinformation or analog data.

When a radio link is used, the contact device houses a radio frequencytransmitter which sends the biosignals to a receiver located nearby withthe signals being processed and digitized for storage and analysis bymicrocomputer systems. When the apparatus of the invention transmitsdata using a radio link, a frequency carrier can be modulated by asubcarrier in a variety of ways: amplitude modulation (AM), frequencymodulation (FM), and code modulation (CM). The subcarriers can bemodulated in a variety of ways which includes AM, FM, pulse amplitudemodulation (PAM), pulse duration modulation (PDM), pulse positionmodulation (PPM), pulse code moduation (PCM), delta modulation (DM), andthe like.

It is understood that the ICL structure and the transducer/transmitterhousing are made of material preferably transparent to radio waves andthe electronic components coated with materials impermeable to fluidsand salts and the whole unit encased in a biocompatable material. Theelectronics, sensors, and battery (whenever an active system is used),are housed in the contact device and are hermetically sealed againstfluid penetration. It is understood that sensors and suitable electrodessuch as for sensing chemicals, pH and the like, will be in directcontact with the tear fluid or the surface of the eye. It is alsounderstood that said sensors, electrodes and the like may be coveredwith suitable permeable membranes according to the application needed.The circuitry and electronics may be encased in wax such as beeswax orparaffin which is not permeable to body fluid. It is understood thatother materials can be used as a moisture barrier. It is also understoodthat various methods and materials can be used as long as there isminimal frequency attenuation, insulation, and biocompatibility. Thecomponents are further encased by biocompatible materials as the onesused in conventional contact lenses such as Hydrogel, silicone, flexibleacrylic, sylastic, or the like.

The transmitter, sensors, and other components can be mounted and/orattached to the contact device using any known attachment techniques,such as gluing, heat-bonding, and the like. The intelligent contact lenscan use a modular construction in its assembly as to allow tailoring thenumber of components by simply adding previously constructed systems tothe contact device.

It is understood that the transmission of data can be accomplished usingpreferably radio link, but other means can also be used. The choice ofwhich energy form to be used by the ICL depends on the transmissionmedium and distance, channel requirement, size of transmitter equipmentand the like. It is understood that the transmission of data from thecontact device by wire can be used but has the disadvantage ofincomplete freedom from attached wires. However, the connection ofsensors by wires to externally placed electronics, amplifiers, and thelike allows housing of larger sensors in the contact device when theapplication requires as well as the reduction of mechanical andelectrical connections in the contact device. The transmission of databy wire can be an important alternative when there is congested spacedue to sensors and electronics in the contact device. It is understoodthat the transmission of data in water from the contact device can bepreferably accomplished using sound energy with a receiver preferablyusing a hydrophone crystal followed by conventional audio frequency FMdecoding.

It is also understood that the transmission of data from the contactdevice can be accomplished by light energy as an alternative to radiofrequency radiation. Optical transmission of signals using all sorts oflight such as visible, infrared, and ultraviolet can be used as acarrier for the transmission of data preferably using infrared light asthe carrier for the transmission system. An LED can be mounted in thecontact device and transmit modulated signals to remotely placedreceivers with the light emitted from the LED being modulated by thesignal. When using this embodiment, the contact device in the receiverunit has the following components: a built in infrared light emitter(950 nm), an infrared detector, decoder, display, and CPU. Prior totransmission, the physiologic variables found on the eye or tear fluidare multiplexed and encoded by pulse interval modulation, pulsefrequency modulation, or the like. The infrared transmitter then emitsshort duration pulses which are sensed by a remotely placed photodiodein the infrared detector which is subsequently decoded, processed, andrecorded. The light transmitted from the LED is received at the opticalreceiver and transformed into electrical signals with subsequentregeneration of the biosignals. Infrared light is reflected quite wellincluding surfaces that do not reflect visible light and can be used inthe transmission of physiological variables and position/motionmeasurement. This embodiment is particularly useful when there islimitations in bandwidth as in radio transmission. Furthermore, thisembodiment may be quite useful with closed eyes since the light can betransmitted through the skin of the eyelid.

It is also understood that the transmission of data from the contactdevice can be accomplished by the use of sound and ultrasound being thepreferred way of transmission underwater since sound is less stronglyattenuated by water than radio waves. The information is transmittedusing modulated sound signals with the sound waves being transmitted toa remote receiver. There is a relatively high absorption of ultrasonicenergy by living tissues, but since the eye even when closed has arather thin intervening tissue the frequency of the ultrasonic energy isnot restricted. However, soundwaves are not the preferred embodimentsince they can take different paths from their source to a receiver withmultiple reflections that can alter the final signal. Furthermore, it isdifficult to transmit rapidly changing biological variables because ofthe relatively low velocity of sound as compared to electromagneticradiation. It is possible though to easily mount an ultrasonicendoradiosonde in the contact device such as for transmitting pH valuesor temperature. An ultrasonic booster transmitter located nearby orcarried by the subject can be used to transmit the signal at a higherpower level. An acoustic tag with a magnetic compass sensor can be usedwith the information acoustically telemetered to a sector scanningsonar.

A preferred embodiment of the invention consists of electrodes, FMtransmitter, and a power supply mounted in the contact device. Stainlesssteel micro cables are used to connect the electronics to thetransducers to the battery power supply. A variety of amplifiers and FMtransmitters including Colpitts oscillator, crystal oscillators andother oscillators preferably utilizing a custom integrated circuitapproach with ultra density circuitry can be used in the apparatus ofthe invention.

Several variables can be simultaneously transmitted using differentfrequencies using several transmitters housed in the contact device.Alternatively, a single transmitter (3 channel transmitter) can transmitcombined voltages to a receiver, with the signal being subsequentlydecoded, separated into three parts, filtered and regenerated as thethree original voltages (different variables such as glucose level,pressure and temperature). A multiple channel system incorporating allsignal processing on a single integrated circuit minimizesinterconnections and can be preferably mounted in the apparatus of theinvention when multiple simultaneous signal transmission is needed suchas transmitting the level of glucose, temperature, bioelectrical, andpressure. A single-chip processor can be combined with a logic chip toalso form a multichannel system for the apparatus of the inventionallowing measurement of several parameters as well as activation oftransducers.

It is understood that a variety of passive, active, and inductive powersources can be used in the apparatus of the invention. The power supplymay consist of micro batteries, inductive power link, energy frombiological sources, nuclear cells, micro power units, fuel cells whichuse glucose and oxygen as energy sources, and the like. The type ofpower source is chosen according to the biological or biophysical eventto be transmitted.

A variety of signal receivers can be used such a frame aerial connectedto a conventional FM receiver from which the signal is amplified decodedand processed. Custom integrated circuits will provide the signalprocessing needed to evaluate the parameters transmitted such astemperature, pressure flow dimensions, bioelectrical activity,concentration of chemical species and the like. The micro transducers,signal processing electronics, transmitters and power source can bebuilt in the contact device.

Power for the system may be supplied from a power cell activated by amicropower control switch contained in the contact device or can beremotely activated by radio frequency means, magnetic means and thelike. Inductive radio frequency powered telemetry in which the same coilsystem used to transfer energy is used for the transmission of datasignal can be used in the apparatus of the invention. The size of thesystem relates primarily to the size of the batteries and thetransmitter. The size of conventional telemetry systems are proportionalto the size of the batteries because most of the volume is occupied bybatteries. The size of the transmitter is related to the operatingfrequency with low frequencies requiring larger components than higherfrequency circuits. Radiation at high frequencies are more attenuatedthan lower frequencies by body tissues. Thus a variety of systemsimplanted inside the body requires lower frequency devices andconsequently larger size components in order for the signal to be lessatenuated. Since the apparatus of the invention is placed on the surfaceof the eye there is little to no attenuation of signals and thus higherfrequency small devices can be used. Furthermore, very small batteriescan be used since the contact device can be easily retrieved and easilyreplaced. The large volume occupied by batteries and power sources inconventional radio telemetry implantable devices can be extremelyreduced since the apparatus of the invention is placed externally on theeye and is of easy access and retrieval, and thus a very small batterycan be utilized and replaced whenever needed.

A variety of system assemblies can be used but the densest systemassembly is preferred such as a hybrid assembly of custom integratedcircuits which permits realization of the signal processing needed forthe applications. The typical resolution of such circuits are in theorder of a few microns and can be easily mounted in the contact device.A variety of parameters can be measured with one integrated circuitwhich translates the signals preferably into a transmission bandwidth.Furthermore, a variety of additional electronics and a complementarymetal oxide semiconductor (CMOS) chip can be mounted in the apparatus ofthe invention for further signal processing and transmission.

The micropower integrated circuits can be utilized with a variety oftransmitter modalities mounted in the intelligent contact lens includingradio links, ultrasonic link and the like. A variety of other integratedcircuits can be mounted in the contact device such as signal processorsfor pressure and temperature, power switches for external control ofimplanted electronics and the like. Pressure transducers such as acapacitive pressure transducer with integral electronics for signalprocessing can be incorporated in the same silicon structure and can bemounted in the contact device. Evolving semiconductor technology andmore sophisticated encoding methods as well as microminiature integratedcircuits amplifiers and receivers are expected to occur and can behoused in the contact device. It is understood that a variety oftransmitters, receivers, and antennas for transmitting and receivingsignals in telemetry can be used in the apparatus of the invention, andhoused in the contact device and/or placed remotely for receiving,processing, and analyzing the signal.

The fluid present on the front surface of the eye covering theconjunctiva and cornea is referred as the tear film or tear fluid. Closeto 100% of the tear film is produced by the lacrimal gland and secretedat a rate of 2 μl/min. The volume of the tear fluid is approximately 10μl. The layer of tear fluid covering the cornea is about 8-10 μm inthickness and the tear fluid covering the conjunctiva is about 15 μmthick. The pre-corneal tear film consists of three layers: a thin lipidlayer measuring about 0.1 μm consisting of the air tear interface, amucin layer measuring 0.03 μm which is in direct contact with thecorneal epithelium, and finally the remaining layer is the thick aqueouslayer which is located between the lipid and mucin layer. The aqueouslayer is primarily derived from the secretions of the lacrimal gland andits chemical composition is very similar to diluted blood with a reducedprotein content and slightly greater osmotic pressure. The secretion andflow of tear fluid from the lacrimal gland located in thesupero-temporal quadrant with the subsequent exit through the lacrimalpuncta located in the infero-medial quadrant creates a continuous flowof tear fluid providing the ideal situation by furnishing a continuoussupply of substrate for one of the stoichiometric reactions which is thesubject of a preferred embodiment for evaluation of glucose levels. Themain component of the tear fluid is the aqueous layer which is anultrafiltrate of blood containing electrolytes such as sodium,potassium, chloride, bicarbonate, calcium, and magnesium as well asamino acids, proteins, enzymes, DNA, lipids, cholesterol, glycoproteins,immunoglobulins, vitamins, minerals and hormones. Moreover, the aqueouslayer also holds critical metabolites such as glucose, urea,catecholamines, and lactate, as well as gases such as oxygen and carbondioxide. Furthermore, any exogenous substances found in the blood streamsuch as drugs, radioactive compounds and the like are present in thetear fluid. Any compound present in the blood can potentiallynoninvasively be evaluated with the apparatus of the invention with thedata transmitted and processed at a remotely located station.

According to one preferred embodiment of the invention, the non-invasiveanalysis of glucose levels will be described: Glucose Detection: —Theapparatus and methods for measurement of blood components and chemicalspecies in the tear fluid and/or surface of the eye is based onelectrodes associated with enzymatic reactions providing an electricalcurrent which can be radio transmitted to a remote receiver providingcontinuous data on the concentration of species in the tear fluid orsurface of the eye. The ICL system is preferably based on a diffusionlimited sensors method that requires no reagents or mechanical/movingparts in the contact device. The preferred method and apparatus of theglucose detector using ICL uses the enzyme glucose oxidase whichcatalyze a reaction involving glucose and oxygen in association withelectrochemical sensors mounted in the contact device that are sensitiveto either the product of the reaction, an endogenous coreactant, or acoupled electron carrier molecule such as the ferrocene-mediated glucosesensors, as well as the direct electrochemical reaction of glucose atthe contact device membrane-covered catalytic metal electrode.

Glucose and oxygen present in the tear fluid either derived from thelacrimal gland or diffused from vessels on the surface of the eye willdiffuse into the contact device reaching an immobilized layer of enzymeglucose oxidase mounted in the contact device. Successful operation ofenzyme electrodes demand constant transport of the substrate to theelectrode since the substrate such as glucose and oxygen are consumedenzymatically. The ICL is the ideal device for using enzyme electrodessince the tear fluid flows continuously on the surface of the eyecreating an optimal environment for providing substrate for thestoichiometric reaction. The ICL besides being a noninvasive systemsolves the critical problem of sensor lifetime which occurs with anysensors that are implanted inside the body. The preferred embodimentrefers to amperometric glucose biosensors with the biosensors based onbiocatalytic oxidation of glucose in the presence of the enzyme oxidase.This is a two step process consisting of enzymatic oxidation of glucoseby glucose oxidase in which the co-factor flavin-adenine dinucleotide(FAD) is reduced to FADH₂ followed by oxidation of the enzyme co-factorby molecular oxygen with formation of hydrogen peroxide.

With catalase enzyme the overall reaction isglucose+2 O₂° gluconic acidGlucose concentration can be measured either by electrochemicaldetection of an increase of the anodic current due to hydrogen peroxide(product of the reaction) oxidation or by detection of the decrease inthe cathodic current due to oxygen (co-reactant) reduction. The ICLglucose detection system preferably has an enzyme electrode in contactwith the tear fluid and/or surface of the eye capable of measuring theoxidation current of hydrogen peroxide created by the stoichiometricconversion of glucose and oxygen in a layer of glucose oxidase mountedinside the contact device. The ICL glucose sensor is preferablyelectrochemical in nature and based on a hydrogen peroxide electrodewhich is converted by immobilized glucose oxidase which generates adirect current depending on the glucose concentration of the tear fluid.

The glucose enzyme electrode of the contact device responds to changesin the concentration of both glucose and oxygen, both of which aresubstrates of the immobilized enzyme glucose oxidase. It is alsounderstood that the sensor in the contact device can be made responsiveto glucose only by operating in a differential mode. The enzymaticelectrodes built in the contact device are placed in contact with thetear fluid or the surface of the eye and the current generated by theelectrodes according to the stoichiometric conversion of glucose, aresubsequently converted to a frequency audio signal and transmitted to aremote receiver, with the current being proportional to the glucoseconcentration according to calibration factors.

The signals can be transmitted using the various transmission systemspreviously described with an externally placed receiver demodulating theaudio frequency signal to a voltage and the glucose concentration beingcalculated from the voltage and subsequently displayed on a LED display.An interface card can be used to connect the receiver with a computerfor further signal processing and analysis. During oxidation of glucoseby glucose oxidase an electrochemically oxidable molecule or any otheroxidable species generated such as hydrogen peroxide can be detectedamperometrically as a current by the electrodes. A preferred embodimentincludes a tree electrode setup consisting of a working electrode(anode) and auxiliary electrode (cathode) and a reference electrodeconnected to an amperometric detector. It should be noted though, that aglucose sensor could function well using two electrodes. Whenappropriate voltage difference is applied between the working andauxiliary electrode, hydrogen peroxide is oxidized on the surface of theworking electrode which creates a measurable electric current. Theintensity of the current generated by the sensor is proportional to theconcentration of hydrogen peroxide which is proportional to theconcentration of glucose in the tear film and the surface of the eye.

A variety of materials can be used for the electrodes such assilver/silver chloride coded cathodes. Anodes may be preferablyconstructed as a platinum wire coated with glucose oxidase or preferablycovered by a immobilized glucose oxidase membrane. Several possibleconfigurations for sensors using amperometric enzyme electrodes whichinvolves detection of oxidable species can be used in the apparatus ofthe invention. A variety of electrodes and setups can be used in thecontact device which are capable of creating a stable working potentialand output current which is proportional to the concentration of bloodcomponents in the tear fluid and surface of the eye. It is understoodthat a variety of electrode setups for the amperometric detection ofoxidable species can be accomplished with the apparatus of theinvention. It is understood that solutions can be applied to the surfaceof the electrodes to enhance transmission.

Other methods which use organic mediators such as ferrocene whichtransfers electrons from glucose oxidase to a base electrode withsubsequent generation of current can be utilized. It is also understoodthat needle-type glucose sensors can be placed in direct contact withthe conjunctiva or encased in a contact device for measurement ofglucose in the tear fluid. It is understood that any sensor capable ofconverting a biological variable to a voltage signal can be used in thecontact device and placed on the surface of the eye for measurement ofthe biological variables. It is understood that any electrodeconfiguration which measures hydrogen peroxide produced in the reactioncatalysed by glucose oxidase can be used in the contact device formeasurement of glucose levels. It is understood that the followingoxygen based enzyme electrode glucose sensor can be used in theapparatus of the invention which is based on the principal that theoxygen not consumed by the enzymatic reactions by catalase enzyme iselectrochemically reduced at an oxygen sensor producing a glucosemodulated oxygen dependent current. This current is compared to acurrent from a similar oxygen sensor without enzymes.

It is understood that the sensors are positioned in a way to optimizethe glucose access to the electrodes such as by creating micro traumasto increase diffusion of glucose across tissues and capillary walls,preferably positioning the sensors against vascularized areas of theeye. In the closed eye about two-thirds of oxygen and glucose comes bydiffusion from the capillaries. Thus positioning the sensors against thepalpebral conjunctiva during blinking can increase the delivery ofsubstrates to the contact device biosensor allowing a useful amount ofsubstrates to diffuse through the contact device biosensor membranes.

There are several locations on the surface of the eye in which the ICLcan be used to measure glucose such as: the tear film laying on thesurface of the cornea which is an ultrafiltrate of blood derived fromthe main lacrimal gland; the tear meniscus which is a reservoir of tearson the edge of the eye lid; the supero-temporal conjunctival fornixwhich allows direct measurement of tears at the origin of secretion; thelimbal area which is a highly vascularized area between cornea and thesclera; and preferably the highly vascularized conjunctiva. The contactdevice allows the most efficient way of acquiring fluid by creatingmicro-damage to the epithelium with a consequent loss of the bloodbarrier function of said epithelium, with the subsequent increase intissue fluid diffusion. Furthermore, mechanical irritation caused by anintentionally constructed slightly rugged surface of the contact devicecan be used in order to increase the flow of substrates. Furthermore, itis understood that a heating element can be mounted in association withthe sensor in order to increase transudation of fluid.

The samples utilized for noninvasive blood analysis may preferably beacquired by micro-traumas to the conjunctiva caused by the contactdevice which has micro projections on its surface in contact with theconjunctiva creating an increase in the diffusion rate of plasmacomponents through the capillary walls toward the measuring sensors.Moreover, the apparatus of the invention may promote increased vascularpermeability of conjunctival vessels through an increase in temperatureusing surface electrodes as heating elements. Furthermore, the sensorsmay be located next to the exit point of the lacrimal gland duct inorder to collect tear fluid close to its origin. Furthermore, thesensors may be placed inferiorly in contact with the conjunctival tearmeniscus which has the largest volume of tear fluid on the surface ofthe eye. Alternatively, the sensors may be placed in contact with thelimbal area which is a substantially vascularized surface of the eye.Any means that create a micro-disruption of the integrity of the ocularsurface or any other means that cause transudation of tissue fluid andconsequently plasma may be used in the invention. Alternatively, thesensors may be placed against he vascularized conjunctiva in thecul-de-sac superiorly or inferiorly.

It is also understood that the sensors can be placed on any location onthe surface of the eye to measure glucose and other chemical compounds.Besides the conventional circular shape of contact lenses, the shape ofthe contact device also includes a flat rectangular configuration, ringlike or half moon like which are used for applications that requireplacement under the palpebral conjunctiva or cul-de-sac of the eye.

A recessed region is created in the contact device for placement of theelectrodes and electronics with enzyme active membranes placed over theelectrodes. A variety of membranes with different permeabilities todifferent chemical species are fitted over the electrodes andenzyme-active membranes. The different permeability of the membranesallows selection of different chemicals to be evaluated and to preventcontaminants from reaching the electrodes. Thus allowing severalelectroactive compounds to be simultaneously evaluated by mountingmembranes with different permeabilities with suitable electrodes on thecontact device.

It is also understood that multilayer membranes with preferentialpermeability to different compounds can be used. The contact deviceencases the microelectrodes forming a bioprotective membrane such thatthe electrodes are covered by the enzyme active membrane which iscovered by the contact device membrane such as polyurethane which isbiocompatable and permeable to the analytes. A membrane between theelectrodes and the enzyme membrane can be used to block interferingsubstances without altering transport of peroxide ion. The permeabilityof the membranes are used to optimize the concentration of the compoundsneeded for the enzymatic reaction and to protect against interferingelements.

It is understood that the diffusion of substrate to the sensor mountedin the contact device is preferably perpendicular to the plane of theelectrode surface. Alternatively, it is understood that the membrane andsurface of the contact device can be constructed to allow selectivenon-perpendicular diffusion of the substrates. It is also understoodthat membranes such as negatively charged perfluorinated ionomer Nafionmembrane can be used in order to reduce interference by electroactivecompounds such as ascorbate, urate and acetaminophen. It is alsounderstood that new polymers and coatings under development which arecapable of preferential selection of electroactive compounds and thatcan prevent degradation of electrodes and enzymes can be used in theapparatus of the invention.

The sensors and membranes coupled with radio transmitters can bepositioned in anyplace in the contact device but may be placed in thecardinal positions in a pie like configuration, with each sensortransmitting its signal to a receiver. For example, if four biologicalvariables are being detected simultaneously the four sensors signals A,B, C, and D are simultaneously transmitted to one or more receivers. Anydevice utilizing the tear fluid to non-invasively measure the bloodcomponents and signals transmitted to a remote station can be used inthe apparatus of the invention. Preferably a small contact device,however any size or shape of contact devices can be used to acquire thedata on the surface of the eye.

An infusion pump can be activated according to the level of glucosedetected by the ICL system and insulin injected automatically as neededto normalize glucose levels as an artificial pancreas. An alarm circuitcan also be coupled with the pump and activated when low or high levelsof glucose are present thus alerting the patient. It is understood thatother drugs, hormones, and chemicals can be detected and signalstransmitted in the same fashion using the apparatus of the invention.

A passive transmitter carrying a resonance circuit can be mounted in thecontact device with its frequency altered by a change in reactance whosemagnitude changes in response to the voltage generated by the glucosesensors. As the signal from passive transmitters falls off extremelyrapidly with distance, the antenna and receiver should be placed near tothe contact device such as in the frame of regular glasses.

It is also understood that active transmitters with batteries housed inthe contact device and suitable sensors as previously described can alsobe used to detect glucose levels. It is also understood that a vibratingmicro-quartz crystal connected to a coil and capable of sending bothsound and radio impulses can be mounted in the contact device andcontinuously transmit data signals related to the concentration ofchemical compounds in the tear fluid.

An oxygen electrode consisting of a platinum cathode and a silver anodeloaded with polarographic voltage can be used in association with theglucose sensor with the radio transmission of the two variables. It isalso understood that sensors which measure oxygen consumption asindirect means of evaluating glucose levels can be used in the apparatusof the invention. The membranes can be used to increase the amount ofoxygen delivered to the membrane enzyme since all glucose oxidasesystems require oxygen and can potentially become oxygen limited. Themembranes also can be made impermeable to other electroactive speciessuch as acetamymophen or substances that can alter the level of hydrogenperoxide produced by the glucose oxidase enzyme membrane.

It is understood that a polarographic Clark-type oxygen detectorelectrode consisting of a platinum cathode in asilver-to-silver-chloride anode with signals telemetered to a remotestation can be used in the apparatus of the invention. It is alsounderstood that other gas sensors using galvanic configuration and thelike can be used with the apparatus of the invention. The oxygen sensoris preferably positioned so as to lodge against the palpebralconjunctiva. The oxygen diffusing across the electrode membrane isreduced at the cathode which produces a electrical current which isconverted to an audio frequency signal and transmitted to a remotestation. The placement of the sensor in the conjunctiva allows intimatecontact with an area vascularized by the same arterial circulation asthe brain which correlates with arterial oxygen and provides anindication of peripheral tissue oxygen. This embodiment allows goodcorrelation between arterial oxygen and cerebral blood flow bymonitoring a tissue bed vascularized by the internal carotid artery, andthus, reflects intracranial oxygenation.

This embodiment can be useful during surgical procedures such as incarotid endarterectomy allowing precise detection of the side withdecreased oxygenation. This same embodiment can be useful in a varietyof heart and brain operations as well as in retinopathy of prematuritywhich allows close observation of the level of oxygen administered andthus prevention of hyperoxia with its potentially blinding effects whilestill delivering adequate amount of oxygen to the infant.

Cholesterol secreted in the tear fluid correlates with plasmacholesterol and a further embodiment utilizes a similar system asdescribed by measurement of glucose. However, this ICL as designed bythe inventor involves an immobilized cholesterol esterase membrane whichsplits cholesterol esters into free cholesterol and fatty acids. Thefree cholesterol passes through selectively permeable membrane to bothfree cholesterol and oxygen and reaches a second membrane consisting ofan immobilized cholesterol oxidase. In the presence of oxygen the freecholesterol is transformed by the cholesterol oxidase into cholestenoneand hydrogen peroxide with the hydrogen peroxide being oxidized on thesurface of the working electrode which creates a measurable electriccurrent with signals preferably converted into audio frequency signalsand transmitted to a remote receiver with the current being proportionalto the cholesterol concentration according to calibration factors. Themethod and apparatus described above relates to the following reactionor part of the following reaction.Cholesterol ester _(cholesterol esterase°) Free cholesterol+fatty acidsFree cholesterol+O_(2cholesterol oxidase°) Cholestenone+H₂O₂

A further embodiment utilizes an antimone electrode that can be housedin the contact device and used to detect the pH and other chemicalspecies of the tear fluid and the surface of the eye. It is alsounderstood that a glass electrode with a transistor circuit capable ofmeasuring pH, pH endoradiosondes, and the like can be used and mountedin the contact device and used for measurement of the pH in the tearfluid or surface of the eye with signals preferably radio transmitted toa remote station.

In another embodiment, catalytic antibodies immobilized in a membranewith associated pH sensitive electrodes can identify a variety ofantigens. The antigen when interacting with the catalytic antibody canpromote the formation of acetic acid with a consequent change in pH andcurrent that is proportional to the concentration of the antigensaccording to calibration factors. In a further embodiment an immobilizedelectrocatalytic active enzyme and associated electrode promote, in thepresence of a substrate (meaning any biological variable), anelectrocatalytic reaction resulting in a current that is proportional tothe amount of said substrate. It is understood that a variety ofenzymatic and nonenzymatic detection systems can be used in theapparatus of the invention.

It is understood that any electrochemical sensor, thermoelectricsensors, acoustic sensors, piezoelectric sensors, optical sensors, andthe like can be mounted in the contact device and placed on the surfaceof the eye for detection and measurement of blood components andphysical parameters found in the eye with signals preferably transmittedto a remote station. It is understood that electrochemical sensors usingamperometric, potentiometric, conductometric, gravimetric, impedimetric,systems, and the like can be used in the apparatus of the invention fordetection and measurement of blood components and physical parametersfound in the eye with signals preferably transmitted to a remotestation.

Some preferable ways have been described; however, any other miniatureradio transmitters can be used and mounted in the contact device and anymicrominiature sensor that modulates a radio transmitter and send thesignal to a nearby radio receiver can be used. Other microminiaturedevices capable of modulating an ultrasound device, or infrared andlaser emitters, and the like can be mounted in the contact device andused for signal detection and transmission to a remote station. Avariety of methods and techniques and devices for gaining andtransmitting information from the eye to a remote receiver can be usedin the apparatus of the invention.

It is an object of the present invention to provide an apparatus andmethod for the non-invasive measurement and evaluation of bloodcomponents.

It is also an object of the present invention to provide an intelligentcontact lens system capable of receiving, processing, and transmittingsignals such as electromagnetic waves, radio waves, infrared and thelike being preferably transmitted to a remote station for signalprocessing and analysis, with transensors and biossensors mounted in thecontact device.

It is a further object of the present invention to detect physicalchanges that occur in the eye, preferably using optical emitters andsensors.

It is a further object of the present invention to provide a novel drugdelivery system for the treatment of eye and systemic diseases.

The above and other objects and advantages will become more readilyapparent when reference is made to the following description taken inconjunction with the accompanying drawings.

The preferred way for evaluation of bodily functions such as diagnosticsand non-invasive blood analysis according to the present inventionincludes placing an intelligent contact lens on the Ahighly vascularizedconjunctiva@. By the present invention it has been discovered that thesurface of the eye and surrounding tissues, in particular theconjunctiva, is the ideal place for diagnostic studies, non-invasiveblood analysis, and health status evaluation. This area provides all ofthe requirements needed for such diagnostics and evaluations includingthe presence of superficially located fenestrated blood vessels. This isthe only area in the body which allows the undisturbed direct view ofblood vessels in their natural state. The present invention allows fluidand cell evaluation and diagnostics to be naturally done using thenormal physiology of the eye and conjunctiva.

The fenestrated blood vessels in the conjunctiva are superficiallylocated and leak plasma. Fenestrated blood vessels have pores and/oropenings in the vessel wall allowing free flow of fluid through itsvessel walls.

According to the principles of the invention, the surface of the eye andthe conjunctiva and surrounding tissues provides the ideal location inthe human body for non-invasive analysis and other fluid and cellulardiagnostics and the preferred way for evaluation of bodily functions andnon-invasive blood analysis. The conjunctiva is the extremely thincontinuous membrane which covers the anterior portion of the eye and eyelid and ends in the limbus at the junction with the cornea and at thejunction of the skin of the eye lid. The conjunctiva is a thintransparent membrane that covers the Awhite@ of the eye as the bulbarconjunctiva and lines the eye lids as the palpebral conjunctiva. Theconjunctiva has a vast network of blood vessels and lies on a secondnetwork of blood vessels on the episclera. The episcleral network ismuch less voluminous than the conjunctival vessel network.

The epithelium of the conjunctiva is a stratified columnar epitheliummade up of only three or less layers of cells, and the middle layer(polygonal cells) is absent in most of the palpebral conjunctiva.Physiologic, anatomic and in-vitro studies by the inventor demonstratedthat the blood vessels in the conjunctiva are fenestrated, meaning havepores, and leak plasma to the surface of the eye and that this plasmacan be evaluated when a device is placed in contact with theconjunctiva. The sensing device can be held by any part of the eye lids,partially when the device is not placed in the cul-de-sac or totallywhen the sensing device is placed in the conjunctival pocket under theeye lid (lower or upper cul-de-sac).

Unlike other tissues covering the body the conjunctiva has a vastnetwork of blood vessels which are superficially located and easilyaccessible. This can be seen by pulling down the lower eye lid andlooking at the red tissue with the actual blood vessels beingvisualized. Those blood vessels and thin membrane are protected by theeye lid and the palpebral conjunctiva is normally hidden behind the eyelids. The blood vessels are in close proximity to the surface and theredness in the tissue is due to the presence of the vast network ofsuperficial blood vessels. This area of the body allows the undisturbeddirect view of the blood vessels. Besides the fact that the bloodvessels have thin walls and are superficially located, those vesselshave a very important and peculiar feature—fenestration with continuousleakage of plasma to the surface of the eye. The plasma continuouslyleaks from the conjunctival blood vessels, and since they aresuperficially located, only a few micrometers have to be traveled bythis fluid to reach the surface of the eye, with the fluid being thenacquired by the diagnostic system of the intelligent contact lens of thepresent invention in apposition to the tissue surface.

Besides the presence of such superficial and fenestrated vessels, theconjunctiva, contrary to the skin, has a thin epithelium with no keratinwhich makes acquisition of signals a much easier process. Moreover, theconjunctiva has little electrical resistance due to the lack of asignificant lipid layer as found in the skin such as the stratum corneumwith a good rate of permeation of substances.

It is important to note that the acquisition of the signal as disclosedby the invention involves a natural occurrence in which the eye lid andsurrounding ocular structures hold the sensing device in directapposition to the conjunctiva. The simple apposition of the intelligentcontact lens to the conjunctiva can create a stimuli for flow toward thesensor and the eye lid; muscular function works as a natural pump.Furthermore, the lack of keratin in the conjunctiva also eliminates acritical barrier creating the most suitable place for evaluation ofbodily functions and non-invasive cell analysis with epithelial, whiteblood cells, and the like being naturally or artificially pumped intothe intelligent contact lens for analysis.

The contact lens according to the principles of the present inventionprovides the ideal structure which is stable, continuous and correctlypositioned against the tissue, in this case the living thin superficiallayer of the thin conjunctiva of the eye. The eye lids provide the onlynatural and superficial means in the body for sensor apposition to thetissues being evaluated without the need for other supporting systemscreating a perfect, continuous and undisturbed natural and physiologiccontact between the sensing devices and tissues due to the naturalanatomy and tension present in the cul-de-sac of the eye lids.

The natural pocket that is formed by the eye lids provides the ideallocation for the undisturbed placement of sensing devices such as theintelligent contact lens of the present invention. Besides providing anundisturbed place for sensor placement and apposition, the natural eyelid pocket provides a place that is out of sight allowing a moredesirable cosmetic appearance in which no hardware is exposed or visibleto another person.

The eye lids are completely internally covered by the conjunctivaallowing a vast double surface, both anterior and posterior surface, tobe used as an area to acquire signals for chemicals, protein and cellevaluation. Furthermore and of vital importance is the fact that the eyelid is also the only place in the body that work as a natural pump offluid to sensing devices.

The eye lid creates a natural pump effect with a force of 25,000 dynes.The force generated by the eye lids is used by the present invention tomove fluids and cells toward sensing devices and works as the onlynatural enhancer to increase fluid transport and cell motion toward asensing device. The pumping and/or tension effect by the eye lid allowsthe fluid or cells to more rapidly reach and permeate the sensorsurface.

The presence of the intelligent contact lens against the conjunctiva inthe conjunctival pocket creates physiologic changes which increases flowand permeation of fluid flux towards the sensor. The lens can be madeirregular which creates friction against the thin and loosely arrangedcell layers of the conjunctiva providing a further increase of flow offluid and cells to the sensor. Since the blood vessels in theconjunctiva are fenestrated and superficial the fluid flows freely fromthe vessels to the surface. This rate of flow can be enhanced by thepresence of the lens and the friction that is created between lenssurface and conjunctiva due to the tension and muscular activity presentin the eye lid. :The free flow of fluid associated with the natural pumpaction of the eye lid moves fluid toward the intelligent contact lenswhich can be used to store such fluid and cells for immediate or laterprocessing.

When the later processing method is used, the partial or completeintelligent contact lens is removed from the eye for further evaluation.A variety of ionization storage areas can be housed in the intelligentcontact lens with the flow of fluid being continuously carried out bythe eye lid pumping action. Furthermore, the conjunctiva provides alarge area for housing the diagnostic systems of the intelligent contactlens with its microchips, microsensors, and hardware for signalacquisition, evaluation, processing and transmission. There is asurprising amount of space in the conjunctiva and its natural pocketsunder the eye lid in each eye. An average of 16 square centimeters ofconjunctival area in the human eye allows enough area for housing thenecessary lens hardware including two natural large pocket formationsunder the lower and upper eye lid. Since the superficial layer of theconjunctiva is a living tissue, contrary to the skin which is deadtissue, a variety of materials can be used in the lens to create theapposition needed by combining hydrophilic and hydrophobic biocompatiblematerial lens surfaces such as hydroxyethylmethacrylate and siliconewhich allow precise balance of material to create the apposition andisolation from contaminants while even creating a suction cup effect toincrease fluid flow.

An exemplary housing of the intelligent contact lens can consist of asurrounding silicone surface which creates adherence around the sensorsurface and thus prevents contaminants to reach the sensor. The fluid orcells to be evaluated are then kept isolated from the remainingenvironment of the eye and any potential contaminant. The remainingportion of the contact lens can be made with hydrogel such ashydroxyethylmethacrylate which is physiologic for the eye. It isunderstood that a variety of lens materials presently used for or laterdeveloped for contact lenses can be used as housing material. Any othernew materials used in conventional contact lenses or intraocular lensescan be used as the housing for the diagnostic systems of the intelligentcontact lens of the present invention. Moreover since the diagnosticintelligent contact lens is preferably placed in the cul-de-sac orconjunctival pocket, there is no problem with oxygen transmissibilityand corneal swelling as occurs with contact lenses placed on the cornea.

Contact lenses placed on the cornea generally cause hypoxic stressleading to corneal swelling when said contact lenses are worn forextended periods of time. The conjunctiva is highly vascularized withinternal supply of oxygen allowing extended wear of the contact lensesplaced in the conjunctival pocket. Contrary to that, the cornea isavascular and requires external supply of oxygen to meet its metabolicneeds.

The high oxygen content present in the conjunctiva is also an advantagefor amperometric sensing systems in which oxygen is used as a substrate.Oxygen is present in lower concentrations in the skin creating animportant limiting factor when using amperometric systems placed on orunder the skin. Similar to the skin, mucosal areas in the body such asoral or gastrointestinal, ear, and nasal passages suffer from equivalentdrawbacks and limitations.

Therefore, preferably, by utilizing a natural physiologic action inwhich there is continuous free flow of fluid through blood vesselsassociated with the continuous tension effect by the lid and a thinpermeable tissue layer such as the conjunctival epithelium, the systemof the invention is capable of providing continuous measurement offluids allowing the creation of a continuous feed-back system. Theintelligent contact lens as described can have magnetic and/or electricelements which are actuated by electrical force or external magneticforces in order to enhance the performance and/or augment the functionsof the system. The dimensions and design for the lens are made in orderto optimize function, comfort, and cosmesis. For example, a length ofless than 4 mm and a height of less than 7 mm for the lower pocket andless than 10 mm for the upper pocket may be used. A thickness of lessthan 2.5 mm, and preferably less than 1.0 mm, would be used. Thediagnostic systems of the intelligent contact lens of the presentinvention is referred to herein as any AICL@ which is primarily used forfluid, chemicals, proteins, molecular or cell diagnosis and the like.

The epithelium of the conjunctiva is very thin and easily accessibleboth M anually and surgically. The layers of the conjunctiva are looselyadherent to the eyeball allowing easy implantation of sensing devicesunderneath said conjunctiva. The intelligent implant of the presentinvention is an alternative embodiment to be used in patients who wantcontinuous measurement of blood components without having to place anICL on the surface of the conjunctiva. The surgical implantation can bedone in the most simple way with a drop of local anesthetic followed bya small incision in the conjunctiva with subsequent placement of thesensing device. The sensing device with its hardware for sensing andtransmission of signals is implanted underneath the conjunctiva or inthe surface of the eye and is continuously bathed by the plasma fluidcoming from the fenestrated conjunctival blood vessels. Although, aconventional power source can be housed in the ICL, the implanted ICLcan be powered by biological sources with energy being acquired from themuscular contraction of the eye muscles. The eye muscles are very activemetabolically and can continuously generate energy by electromechanicalmeans. In this embodiment the eye lid muscle and/or extra-ocular musclewhich lies underneath the conjunctiva is connected to a power transducerhoused in the ICL which converts the muscular work into electricalenergy which can be subsequently stored in a standard energy storagemedium.

Besides the exemplary electromechanical energy source, other powersources that are suitable for both implanted and externally placed ICLswould include lightweight thin plastic batteries. These batteries use acombination of plastics such as fluorophenylthiophenes as electrodes andare flexible allowing better conformation with the anatomy of the eye.

Another exemplary suitable power source includes a light weightultra-thin solid state lithium battery comprised of a semisolid plasticelectrolyte which are about 150 μm thick and well suited for use in theICL. The power supply can also be inactive in order to preserve energywith a switch triggered by muscle action whenever measurement is neededaccording to patient=s individual condition.

The implanted ICL provides continuous measurement of analytes creating acontinuous feed-back system. A long-term implanted ICL can be usedwithout the need for replacement of reagents. As an alternativeimplanted ICLs can use enzymatic systems that require replacement ofenzymes and when such alternative embodiment is used the whole implantedICL can be removed or simply a cartridge can be exchanged or enzymaticmaterial inserted through the ICL housing into its appropriate place.All of this manipulation for implanted ICLs can be easily done with asimple drop of anesthetic since the conjunctival area is easilyaccessible. Contrary to the skin which is non-transparent, theconjunctiva is transparent allowing easy visualization of the implantedICL. Contrary to other parts of the body the procedure can be done in avirtually bloodless manner for both insertion, removal and replacementif needed.

It is important to note that previously, after removing blood from apatient, major laboratory analysis was required consisting of theseparation of blood components to acquire plasma. In the case of theconjunctiva and the eye, according to the principles of the invention,the body itself deliver the plasma already separated for measurement andfreely flowing to the ICL sensing device externally or internally(surgically) placed. To further create the perfect location forevaluation of bodily functions, the conjunctival area is poorlyinnervated which allows placement of the ICL in the conjunctival sac forlong periods of time with no sensation of discomfort by the user. Thereare only few pain fibers, but no pressure fibers in the conjunctiva.Furthermore, as mentioned, there is a vast amount of space under thelids allowing multiple sensing devices and other hardware to be placedin the conjunctival area.

To further provide the perfect location for measurements of fluid andcells, the sensing device can be held in place by the eye lid creatingthe perfect apposition between the surface of the eye and the ICLsensor. Since the blood vessels are superficially located, only a fewmicrometers have to be traveled by the fluid to reach the surface of theeye, with the fluid being then acquired by the ICL in apposition to thetissue surface. No other organ has the advantage of the natural pocketof the eye lid to secure a sensor in position and apposition naturallywithout need of other devices or external forces. A combination of ahydrophobic and a hydrophilic surface of the ICL housing creates thestability that is needed for the ICL to remain in any type of appositionto the conjunctival surface, meaning more tightly adherent or lessadherent to the conjunctival surface according to the evaluation beingcarried out. To further create the prefect environment for evaluation ofblood components, the eye lid during blinking or closure, creates a pumpeffect which is an adjunctive in directing the plasma components towardthe sensor.

The present invention uses plasma, but non-invasively. Furthermore,contrary to the finger, the ocular surface evaluated by the system ofthe present invention is irrigated by a direct branch from the carotidartery allowing the direct evaluation of brain analyte level. The brainanalyte level is the most important value for the evaluation of themetabolic state of a patient.

The cells of the epithelium of the conjunctiva are alive and looselyadherent allowing cell analysis to be performed using the ICL, contraryto the skin surface which is dead. The ICL can naturally remove thecells from the surface during the action of the eye lid or by mechanicalpumping means or electrical means and then living cells can then beextracted for further evaluation within the ICL or outside the ICL.Appropriate membrane surfaces are used to separate cells components andfluid components. Different permeabilities of membranes in apposition tothe conjunctiva are used according to the function that is carried outor the function of a particular ICL.

The present invention brings not only innovation but also acost-effective system allowing diagnostic and blood evaluation to bedone in a way never possible before. The current invention allowsunbelievable savings for the patient, government and society in general.An ICL can be disposable and provide continuous measurement over 24hours and costs to the user around $5 to $8 dollars for one single ormultiple testing ICL (meaning more than one analyte is evaluated). Thematerial used in the ICL includes an inexpensive polymer. The reagentsand/or enzymatic membranes are used in very small quantities and arealso thus inexpensive, and the electronics, integrated circuits andtransmitter are common and fairly inexpensive when mass produced as isdone with conventional chips.

The current invention provides means to better control health careexpenditure by delivering systems that are astonishingly 20 timescheaper than the prior art using a variety of means ranging fromlow-cost amperometric systems to disposable microfluidic chips andintegration of biochemical and disposable silicon chip technologies intothe ICLs. The ICLs can perform numerous analysis per lens and if justone more test is performed the cost of ICL remains about the same sincethe new reagents are used in minute quantities and the similarelectronics can be used in the same ICL. In this case, with dual testing(two tests per lens, four times a day) the ICL is a staggering 100 timescheaper.

The system of the invention allows a life-saving technologicalinnovation to help contain health care costs and thus enhance theoverall economy of the nation, as well as to not only provide atechnological innovation that can be used in industrialized nations butalso in economically challenged countries, ultimately allowinglife-saving diagnostic and monitoring biological data to be accessiblein a cost-effective and wide-spread manner. Moreover, this affordablesystem allows not only individual measurements but also continuous 24hour non-invasive measurement of analytes including during sleeping,allowing thus the creation of an artificial organ with preciselytailored delivery of medications according to the analyte levels.

Although the ICL externally placed is the preferred way, a surgicalimplant for continuous monitoring is a suitable alternative embodimentas described above. Furthermore, it is understood that a small rod withsensing devices housed in the tip can be used. In that embodiment thepatient places the sensor against the conjunctiva after pulling the eyelid down and exposing the red part and then applying the sensing deviceagainst it for measurement. Alternatively, the tip of the rod is lightlyrubbed against the conjunctiva to create microdisruption as naturallycaused by the eyelid tension, and then the sensing device is applied andthe sensor activated for measurement. It is understood that any othermeans to promote or increase transudation of plasma in the conjunctivacan be used with the ICL, including, but not limited to heating systems,creating a reverse electroosmotic flow, electrophoresis, application ofcurrent, ultrasonic waves as well as chemical enhancers of flow,electroporation and other means to increase permeation.

An exemplary embodiment of the diagnostic ICLs provides a continuousmeasurement of the analyte by means of biosensing technology. These ICLbiosensors are compact analytical devices combining a biological sensingelement coupled with a physicochemical transducer which produces acontinuous or discrete electronic signal that is proportional to theconcentration of the elements or group of elements being evaluated. Thediagnostic ICLs then can continuously measure the presence or theabsence of organic and inorganic elements in a rapid, accurate, compactand low-cost manner. A variety of biosensors can be used as previouslydescribed including amperometric with other conventional parts as highimpedance amplifiers with associated power supply as well aspotentiometric, conductometric, impedimetric, optical, immunosensors,piezoimmunobiosensor, other physicocehmical biosensors and the like.

Some of the amperometric systems described produce a current generatedwhen electrons are exchanged between a biological system and anelectrode as the non-invasive glucose measuring system referred toherein as AGlucoLens@. The potentiometric ICLs measure the accumulationof charge density at the surface of an electrode as in ion-selectivefield-effect transistors (ISFET) such as for measuring sodium,potassium, ionized calcium, chloride, gases as carbon dioxide, pH, andthe like present in the eye.

Optical diagnostic biosensors ICL correlates the changes in the mass orconcentration of the element with changes in the characteristic of thelight. It is also understood that the diagnostic ICLs can utilize otherforms for biosensing such as changes in ionic conductance, enthalpy,mass as well as immunobiointeractions and the like.

The miniaturization and integration of biochemical/chemical systems andmicroelectronic technologies can provide the microscopic analyticalsystems with integrated biochemical processing that are housed in theICLs for fluid and cell evaluation. ICLs can then perform all of thesteps used in a conventional laboratory using minute amounts of reagentsbeing capable of evaluating any blood, plasma or tissue components.Advances in nanotechnology, micro and nanoscale fabrication,nanoelectronics, Asmart dust@ and the like will create systems ofinfinitely small dimensions which can be used in ICLs allowing multiplefluid and cell evaluation to be done simultaneously in one single ICL.Therefore, thicknesses of less than 0.5 mm for the ICL are likely.

Another exemplary embodiment of the diagnostic ICLs provide chemical,genetic, and other analytical evaluations using microfabricatedbioelectronic chips with the acquisition of biochemical and chemicalinformation using microsystems with microfabrication of chemicalintegrated circuits and other silicon chip biochemical technologies.ICLs can house a variety of microscopic means for fluid and cellhandling and biochemical processing devices. Diagnostic ICLs provide acomplete analysis of the fluid and cells being acquired from the eyewith elements being transported into the ICL for analysis according tothe principles of the invention.

In this embodiment the ICL comprises a microchip using microfluidics andchemical/biochemical microchip technology creating a complete chemicalprocessing system. Using electrical impulses the ICLs can activelydirect small quantities of fluid to different parts of the ICL structurein fractions of a second for further analysis in a completely automatedway with the detectable signal result being preferably radiotransmittedto a remote station according to the principles of the invention.

The ICL biomicrochips can be produced using photolithography, chemicaletching techniques and silicon chip technologies similar to those usedin the manufacture of computer chips. The ICL system thus achieve theminiaturization needed for the ICL dimensions with microchannels etchedinto the chip substrate measuring up to 100 micrometers, and preferablyup to 10 micrometers in depth, by 1 to 500 micrometers, and preferably10 to 100 micrometers wide.

The microchannels carry the fluid and cells from the eye and havereservoirs and chambers with the reagents and sample solutions neededfor analysis. The ICL radio frequency transceivers comprisemicroelectronic systems with radio frequency integrated circuitsallowing the small dimensions to be achieved for incorporation into theICL.

A variety of power sources have been described, but in order to minimizehardware and cost of the ICL, an ultra-capacitor charged externallythrough electromagnetic induction coupling can be used instead of thepolymer microbatteries or rechargeable batteries. Although there is anenormous amount of space in the conjunctival area, with two largepockets in each eye as described, allowing much larger systems to beused, it is preferable that the most miniaturized system be used whichthen allows multiple tests to be simultaneously performed.

The exemplary ICL embodiments contain on a microscopic scale equivalentelements to all of the elements found in conventional laboratories suchas pumps, valves, beakers, separation equipment, and extractors,allowing virtually any chemical preparation, manipulation and detectionof analytes to be performed in the ICLs. The pumps, reactors, electricalvalves, filters, sample preparation can be created preferably by theapplication of electrical charges and piezoelectric charges to thechannels and structure of the ICL allowing directing of fluid to anypart of the ICL structure as needed, coupled to the analysis of thematerial with the completion of numerous biochemical, cell-based assays,and nucleic acid assays. Current and future advances in microfluidics,electrically conducting liquids, microcapillary electrophoresis,electrospray technology, nanofluidics, ultrafine particles, andnanoscale fabrication allows the creation of several analytical systemwithin one single ICL with the concomitant analysis of cancer markers,heart markers, DNA mutations, glucose level, detection of infectiousagents such as bacteria, virus, and the like using samples from the eyein the microliter and picoliter scales.

Diagnostic ICLs can perform molecular separations using numeroustechniques. Complete clinical chemistry, biochemical analysis, nucleicacid separation, immunoassays, and cellular processing, can be performedon a continuous manner by using the appropriate integration of chip withbiochemical processing and associated remote transmission associatedwith the continuous flow of fluid and cells from the eye. ICLs containnumerous elements for a variety of microfluidic manipulation andseparation of plasma or fluid components acquired from the surface ofthe eye for chemical analysis. Since there is a continuous flow of fluidfrom the conjunctival surface to the sensing devices and systems in theICL, the sensing devices and systems can perform continuous biochemicalevaluation while moving minute amounts of fluid through the microscopicchannels present in a microchip contained in the structure of the ICL.

A variety of chemical microchips can be used creating motion of fluidthrough microchannels using electrokinetic forces generated within thestructure of the ICL. Microwires, power sources, electrical circuits andcontrollers with the associated electronics generate certain changes inelectrical Voltage across portions of the microchip which controls theflow rate and direction of the fluid in the various channels and partsof the microchip housed in the structure of the ICL creating anautomated handling of fluids within the ICL and a complete chemicalprocessing systems within the ICL, preferably without any moving partswithin the ICL structure. However, micropumps, microvalves, othermicroelectrical and mechanical systems (MEMS) and the like can be usedin the present invention.

The ICLs provide a cost-effective system which can be broadly androutinely used for a range of classical screening applications,functional cell-based assays, enzyme assays, immunoassays, clinicalchemistry such as testing for glucose, electrolytes, enzymes, proteins,and lipids; as well as toxicology and the like in both civilian andmilitary environments. A critical element in the battlefield in thefuture will be the detection of biological or chemical weapons. One ofthe ways to detect the use of weapons by enemy forces unfortunatelyrelies on detection of immediate illness and most often, later afterillness is spreading, since some of the damaging effects do not elicitimmediate symptoms and cause serious damage until time goes on. Troopscan use an ICL with detection systems for the most commonchemical/biological weapons. The ICLs create a 24 hour surveillancesystem identifying any insulting element, even in minute amounts,allowing proper actions and preventive measures to be taken beforeirreversible or more serious damage occur.

A dual system ICL with tracking and chemical sensing can be an importantembodiment in the battlefield as troops exposed to chemical weapons arenot only identified as exposed to chemical weapons but also immediatelylocated. In this exemplary embodiment the ICL position can be locatedusing for instance Global Positioning System (GPS), fixed frequency, orthe like. The GPS is a sophisticated satellite-based positioning systeminitially built in the mid-1970s by the United States Department ofDefense to be used primarily in military operations to indicate theposition of a receiver on the ground. Radio pulses as spheres ofposition from the satellites in orbit intersect with the surface of theearth marking the transceiver exact position. ICL transceivers forinstance in one eye determines position and a chemical sensing ICL inthe other eye determines a chemical compound. Besides being placedexternally in the eye, during military use, the ICL, both tracking andchemical sensing, can be easily and temporarily surgically implanted inthe conjunctival pocket.

A surveillance system can be used in the civilian environment as forinstance detecting the presence of tumor markers, cardiac markers,infectious agents and the like. Very frequently the body providesinformation in the form of markers before some serious illnesses occurbut unfortunately those markers are not identified on a timely fashion.It is known that certain tumors release markers and chemicals beforegoing out of control and creating generalized damage and spread. Ifpatients could have access to those blood tests on a timely fashion,many cancers could be eliminated before causing irreversible andwidespread damage.

For example patients at risk for certain cancers can use the ICL on aroutine basis for the detection of markers related to the cancers. Themarkers that appear when the cancer is spreading or becoming out ofcontrol by the body immune system can then be detected.

The same applies to a variety of disorders including heart attacks.Thus, if a patient has a family history of heart disease, has highcholesterol or high blood pressure, the patient uses the ICL for cardiacmarkers on a periodic basis in order to detect the presence of markersbefore a potentially fatal event, such as a heart attack, occurs.

A temperature sensing ICL, as previously described, can be coupled withan infection-detecting system in patients at risk for infection such aspost-transplant recovery or undergoing chemotherapy. The temperaturesensing ICL continuously monitors the temperature and as soon as atemperature spike occurs it activates the cell sensing ICL to detect thepresence of infectious agents. The conjunctival surface is an idealplace for continuous temperature measurement by allowing measurement ofcore temperature without the need to use a somehow invasive and/oruncomfortable means.

As micro and nanofabrication evolves, a variety of analytes and physicalchanges, such as for instance temperature changes, can be evaluated withone single ICL with fluid and tissue specimens being directed toparallel systems allowing multiple assays and chemical analysis to beperformed in one individual ICL. By using both eyes and the upper andlower eye lid pockets of each eye a large of number of testing andmonitoring means can be achieved at the same time by each patient,ultimately -replacing entire conventional laboratories while providinglife-saving information.

While sleeping chemical and physical signs can be identified with theICL which can remain in place in the eye in intimate contact with notonly the body, chemically and physically, but also in direct contactwith the two main vital organs, the brain and the heart. A single ICL ora combination of an ICL to detect physical changes and a chemical ICLcan detect markers related to sudden death and/or changes in blood gas,brain and heart activity, and the like. If timely identified many ofthose situations related to unexplained death or sudden death can betreated and lives preserved.

The type of ICL can be tailored to the individual needs of a patient,for instance a patient with heart disease or family history of heartdisease or sudden death can use an ICL for detection of elements relatedto the heart. Since the ICLs are primarily designed to be placed on theconjunctiva in the eye lid pocket, there is virtually no risk for theeye or decreased oxygenation in the cornea due to sleeping with a lens.Thus, another advantage of the present invention is to provide physicaland chemical analysis while the user is sleeping.

Another combination of ICLs systems concerns the ICL which identifiesthe transition between sleep and arousal states. It is impossible forhuman beings to know the exact time one falls asleep. One may know whattime one went to bed, but the moment of falling asleep is not part ofthe conscious mind. The reticular formation in the brain controls thearousal state. Interestingly, that brain function is connected with aneye function, the Bell phenomena. An alarm system to prevent the userfrom falling asleep (referred herein as Alert ICL), for example whiledriving or operating machinery may be used. In another exemplaryembodiment, the Alert ICL is coupled to a Therapeutic ICL to releaseminute amounts of a drug that keeps the patient alert and oriented.

The fluid in the tissue or surface of the eye is continuously loadedinto the ICL chip preferably associated with the pump action of the eyelid but alternatively by diffusion or electrokinetically at presetperiods of time such as every 30 minutes in order to preserve reagentspresent in the ICL microchip. A selective permeable membrane and/or aone-way microvalve can separate the compounds before they are loadedinto the microchannels in the ICL chip. Plasma and other fluids andcells can be electrically directed from the ocular tissue to the ICLsensing system and using electrical charges present or artificiallycreated in the molecules or by electromagnetic means multiple orindividual compounds can be directed to the ICL. The fluid and/or cellwith its individual substances reaches and selectively permeates the ICLsurface for analysis allowing specific compounds to be acquiredaccording to the ICL analytical system and reagents present. One of theprinciples related to the movement of fluid through the microchannels isbased on capillary electrophoresis.

The eye fluid for analysis flow through microscopic channels housed inthe ICL with the direction of flow being controlled by electrical orelectromagnetic means with changes in the configuration of electricalfields dynamically moving substances to a particular direction and thevoltage gradient determining the concentration and location of thesubstance along the channels. In an exemplary embodimentmicroelectrophoresis is used for chemical analysis with separation ofthe molecules according to their electrical charge and mass as well assimple diffusion with the consequent motion and separation of thesubstances for analysis.

Besides performing complete chemical processing and analysis, the systemof the invention uses DNA or genetic chips in the micro and nanoarraydimensions and microfabricated capillary electrophoresis chips todiagnose genetically based diseases using the fluid and cells flowing tothe ICL present in the conjunctival pocket. The ICL provides acost-effective and innovative way to do screening and monitor therapy.DNA-chip systems in the ICL can perform all the processing and analysisof fluids preferably using capillary electrophoresis. A variety of knownDNA chips and other emerging technology in DNA chips can be used in theICL including, but not limited to, sequencing chips, expression chips,and the like. PCR (polymerase chain reaction) can be done much morerapidly on a micro scale as with the ICL design.

The ICL microchip can have an array of DNA probes and use electricalfields to move and concentrate the sample DNA to specific sites on theICL microchip. These genetic ICLs can be used for diagnosing diseaseslinked to particular genetic expressions or aberrant genetic expressionsusing cells and/or fluid acquired by the ICL according to the principlesof the invention.

For instance, the gene p450 and its eight different expressions, ormutations have been associated with a variety of cancers. Numerousoncogenes and tumor-suppressor genes can be detected by using the priorart with the conventional removal of blood, although the yield is verylow because of the limitation of sample collected at only one point intime. It is very difficult to find a tumor cell, chemical change ormarker among millions of cells or chemical compounds present in oneblood sample acquired at one point in time. The prior art collects oneblood sample and analyzes the sample in an attempt to find markers orother chemical and cell changes. As one can see it is by chance that onecan actually find a marker. Thus even after removing blood, sending itto the laboratory and analyzing the sample the result of this expensiveprocedure may be negative regardless of the fact of the patient actuallyhas the occult cancer or risk for a heart attack. These false negativesoccur because the sample is acquired in one point in time. Furthermoreeven if several blood samples are acquired over several hours which ispractically impossible and painful, the prior art has to detectcompounds and cells at very low concentrations and would have thus toperform several analysis isolating small samples to try to increase theyield.

With the system of the present invention there is continuous flow ofanalytes, cell and fluid to the ICL chips with the ICLs working on acontinuous mode to search for the marker 24 hours a day. The fluid iscontinuously acquired, processed within the ICL with subsequentreabsorption of the fluid and cells by the surface of the eye.

Please note that because the surface of the eye is composed of livingtissue, contrary to the skin in which the keratin that covers said skinis dead, a completely recycled system can be created. The fluid andcells move to the ICL and are analyzed in microamounts as they passthrough the microchannels, network of channels, and detection systems,and if for instance a marker is found, the signal is wirelesslytransmitted to a remote receiver. The fluid then continues its movementtoward the place for reabsorption according to its diffusing propertiesor moved by electrokinetic forces applied within the structure andchannels of the ICL chip. In this manner, large amounts of sample fluid(although still nanoliters going through the microchannels) can be veryprecisely and finely analyzed as an ultrafiltrate going through a finesieve. The fluid flows through the chip with the chip continuouslycapturing fluid and cells for a variety of chemical analysis includinggenetic analysis since the continuous flow allows concentrating nucleicacid for analysis as it passes, for example, through the array structurein the chip.

Although selectively permeable membranes can be used to retain any toxicreagent, and those reagents are used in the picoliter and nanoliterrange, alternatively, a disposal chamber can be used with the fluid andcells remaining in the ICL until being removed from the eye, forinstance after 24 to 48 hours. In the case of a very complex DNAanalysis still not available in the ICL, the ICL can be alternativelytransferred to conventional macro equipment after the eye fluid isacquired, but preferably the complete analysis is done within the ICLwith signals transmitted to a remote station.

A variety of matrix and membranes with different permeabilities and poresizes are used in the channels in order to size and separate cells andpieces of DNA. The continuous analysis provided by the system provides areliable way for the detection of oncogenes and tumor suppressing genesestablishing a correlation between measurable molecular changes andcritical clinical findings such as cancer progression and response totherapy allowing a painless and bloodless surveillance system to becreated. As the Human Genome Project further identify markers and genes,the system of the invention can provide a noninvasive, inexpensive,widespread analysis and detection system by comfortably using acosmetically acceptable device being hidden under the eye lids or placedon the surface of the eye, but preferably placed in any of the pocketsnaturally formed by the anatomy of the eye lids.

The control of electrical signals applied within the structure of theICLs are microprocessor-based allowing an enormous amount ofcombinations of fluid and cell motion to be achieved and the finestcontrol of fluid motion within precise and specific time frames such asmoving positive charges to a certain microchannel and waiting a certainamount of time until reaction and processing occurs, and thenredirecting the remaining fluid for further processing at anotherlocation within the ICL, then mixing reagents and waiting a fixed amountof time until a new electrical signal is applied, in the same manner aswith semiconductor chips. The processing then is followed by separationof the products of the reaction and/or generation of a detectablesignal, and then further electrical energy is applied redirecting theremaining fluid to a disposal reservoir or to be reabsorbed by theocular surface. The cycle repeats again and as fluid is reabsorbed orleaves the system, more fluid on the other end is moved toward the ICLaccording to the principles described.

The ICLs accomplish these repetitive functions and analysis quickly andinexpensively using the charged or ionic characteristics of fluid, cellsand substances with electrodes applying a certain voltage to move cellsand fluids through the ICL microchannels and reservoirs. The ICLs can bedesigned according to the type of assay performed with electricalsignals being modified according to the function and analysis desired ascontrolled by the microprocessor including the timing of the reactions,sample preparation and the like. An ICL can be designed with certainsensor and reagent systems such as for instance amperometric, optical,immunologic, and the like depending on the compound being analyzed. Theonly limiting factor is consumption of reagents which can be replaced,or a cartridge-based format used, or preferably as a disposable unit.Since the ICL is low-cost and is easily accessible manually simply bypulling down the eyelid, the complete ICL can work as a disposable unitand be replaced as needed.

The design of the ICL is done in a way to optimize fluid flow andliquid-surface interaction and the channels can be createdphotolithographically in either silicon, glass, or plastic substratesand the like as well as combining chip technology and microbiosensorswith microelectronics and mechanical systems. Each ICL is preloaded withreagents, antigens, antibodies, buffer, and the like according to theanalysis to be performed and each reservoir on an ICL chip can be asource of enzymatic membranes, buffers, enzymes, ligand inhibitors,antigens, antibodies, substrates, DNA inhibitor, and the like. Themovement of fluids in the ICL can be accomplished mechanically as withthe lid pumping action, non-mechanically, electrically or as acombination.

The microstructures incorporated in the ICLs can efficiently capture andmove fluids and/or cells using the physiological pump action of the eyelids and/or by using electrical charges to move and direct specificcompounds toward specific sensors or detection units using nanolitervolume of the biological sample and taking these minute sample volumesand then moving them through the various stages of sample preparation,detection, and analysis. The ICL system moves a measured and precisevolume of fluid according to the time that the voltage is applied to thechannels and the size of the channels. In the ICL microfluidics chipsthe fluid motion is primarily derived from electrokinetic forces as aresult of voltages that are applied to specific parts of the chip.

A combination of electroosmosis and electrophoresis moves bulk amountsof fluid along the channels according to the application of anelectrical field along the channel while molecules are moved to aparticular microelectrode depending on the charge of the molecule or/andaccording to its transport and diffusion properties. In electrophoresisthe application of voltage gradient causes the ions present in the eyefluid to migrate toward an oppositely charged electrode.

Electroosmosis relates to the surface charge on the walls of themicrochannels with a negative wall attracting positive ions. Then whenvoltage is applied across the microchannel the cations migrate in thedirection of the cathode resulting in a net flow of the fluid in thedirection of the negative electrode with a uniform flow velocity acrossthe entire channel diameter.

By applying voltages to various channel intersections, the ICL chipmoves the eye fluid through the system of microchannels and/or microarray systems, adjusting its concentration, diluting, mixing it withbuffers, fragmenting cells by electrical discharge, separating out theconstituents, adding fluorescent tags and directing the sample pastdetection devices. The eye fluid can then, after processing, be moved tothe detection units within the ICL. Numerous sensing devices andtechniques can be used as part of the analysis/detection system withcreation of an optically detectable or encoded substance,chromatographic techniques, electrochemical, reaction with antibodiesplaced within the structure of the ICL with the subsequent creation ofan end signal such as electrical current, change in voltage, and thelike, with the signal wirelessly transmitted to a remote receiver. Thecurrent invention allows all of the steps to be performed for datageneration including acquisition, processing, transmission and analysisof the signal with one device, the ICL.

A variety of processes and apparatus can be used for manufacturing ICLsincluding casting, molding, spin-cast, lathing and the like. Anexemplary embodiment for low-cost mass production of the ICL consists ofproduction of the detection and transmission hardware (chemicalmicrochips, processor, transmitter, power supply) as one unit(sheet-like) for instance mounted in polyamide or other suitablematerial. The sheet then, which can have different shapes, butpreferably a rectangular or ring-like configuration, is placed inside acavity defined between moulding surfaces of conventional contact lensmanufacturing apparatus. The moulding surfaces and cavity determine theshape and thickness of the ICL to be produced according to the functionneeded.

However, an ICL placed in an eye lid pocket or an annular ring contactlens will have a maximum thickness of 2.5 mm, preferably less than 1.0mm. An oversized round or regular round contact lens configurationhaving a diameter of less than 3 cm for an oversize contact lens and adiameter less than 12 mm for a regular contact lens, will have a maximumthickness of 1.0 mm, and preferably less than 0.5 mm.

After the hardware above is in the cavity, the lens polymer is dispensedinto the cavity with subsequent polymerization of the lens material asfor instance with the use of heat, ultra-violet light, or by using twomaterials which in contact trigger polymerization. Accordingly, the ICLscan be manufactured in very large quantities and inexpensively usingmoulding techniques in which no machining is necessary. Although oneexemplary preferred embodiment is described it is understood that avariety of manufacturing means and processes for manufacturing of lensescan be used and other materials such as already polymerized plastic,thermoplastic, silicone, and the like can be used.

The ICL diagnostic system of the exemplary embodiment above describedconsists of an integration of chemical chips, microprocessors,transmitters, chemical sensing, tracking, temperature and otherdetecting devices incorporated within the structure of the contactdevice placed in the eye. Although the system preferably uses tissuefluid and cells, and plasma for analysis, it is understood that thereare certain markers, cells or chemical compounds present in the actualtear film that can be analyzed in the same fashion using a contact lensbased system.

The present invention allows the user to perform life-saving testingwhile doing their daily routines: one can have an ICL in the eyedetecting an occult breast cancer marker while driving, or diagnosingthe presence of an infectious agent or mutation of a viral gene whiledoing groceries (if the mutation is detected in the patient, it can betreated on a timely fashion with the appropriate drug), while workinghaving routine clinical chemistry done, or while eating in a restaurantdetecting a marker for prostate cancer in one eye and a marker for heartattack in the other eye before heart damage and sudden death occurs, orone can have an ICL placed in the eye detecting genetic markers whilechecking their GPI e-mail with a computer arrangement. In this lastembodiment, the computer screen can power the ICL electromagneticallywhile the user checks their GPI e-mail.

Furthermore, diabetics can monitor their disease while playing golf, anda parent with high blood pressure can have ICLs in their eyes detectingstroke and heart markers while playing with their children in thecomfort of their homes and without having to spend time, money, andeffort to go to a hospital for testing with drawing of blood as isconventionally done.

The ICL can besides performing tests in-situ also collect the eye fluidfor further analysis as one is working in the office over an eight hourperiod in a comfortable and undisturbed manner by having the ICL in theeye lid pocket. In this last exemplary-embodiment the user sends the ICLto the laboratory for further processing if needed, but still samplingwas done without the user having to go to a doctor, devote timeexclusively for the test, endure pain with a needle stick, endure therisk of infection and the costs associated with the procedure.

Moreover, the ICL system provides a 24 hour continuous surveillancesystem for the presence of, for instance, cancer markers before thecancer is clinically identifiable, meaning identified by the doctor orby symptoms experienced by the patient. The ICL system of the currentinvention can pump eye fluid and cells into the ICL continuously formany days at a time creating thus a continuous monitoring system and assoon as the marker is identified a signal is transmitted. For example ifa reaction chamber X in the ICL is coated with electrocatalyticantibodies for a breast cancer marker, then once the marker is presentan electrical signal is created in the chamber X indicating that abreast cancer or prostate cancer for instance was identified.

Most cancers kill because they are silent and identified only when inadvanced stages. Thus the ICL system provides the ideal surveillancesystem potentially allowing life-expectancy in general to increaseassociated with the extra benefit of the obvious decrease in health carecosts related which occurs when treating complicated and advancedcancers. In addition, the present invention provides all of theselife-saving, cost-saving and time-saving features in a painless mannerwithout anyone even knowing one is checking for a cancer marker, heartdisease marker, infectious agent, blood sugar levels and so forth sincethe ICL is conveniently and naturally hidden under the eye lid workingas your Personal Invisible Laboratory (PIL).

It is an object of the present invention to address the above needs inthe art and provide the accuracy and precision needed for clinicalapplication by being able to eliminate or substantially reduce thesources of errors, interference, and variability found in the prior art.By greatly reducing or eliminating the interfering constituents andproviding a much higher signal to noise ratio, the present invention canprovide the answers and results needed for accurate and precisemeasurement of chemical components in vivo using optical means such asinfrared spectroscopy. Moreover, the apparatus and methods of thepresent invention by enhancing the signal allows clinical usefulreadings to be obtained with various techniques and using differenttypes of electromagnetic radiation. Besides near-infrared spectroscopy,the present invention provides superior results and higher signal tonoise ratio when using any other form of electromagnetic radiation suchas for example mid-infrared radiation, radio wave impedance,photoacoustic spectroscopy, Raman spectroscopy, visible spectroscopy,ultraviolet spectroscopy, fluorescent spectroscopy, scatteringspectroscopy, and optical rotation of polarized light as well as othertechniques such as fluorescent (including Maillard reaction, lightinduced fluorescence, and induction of glucose fluorescence byultraviolet light), colorimetric, refractive index, light reflection,thermal gradient, Attenuated Total Internal Reflection, molecularimprinting, and the like.

It is a further object of the present invention to provide methods andapparatus for measuring a substance of interest using natural bodyfar-infrared emissions which occur in a thermally stable environmentsuch as in the eyelid pocket.

Still a further object of the invention is to provide an apparatus andmethod that allows direct application of Beer-Lambert's law in-vivo.

Yet a further object is to provide a method and apparatus for continuousmeasurement of core temperature in a thermally stable environment.

By the present invention, the discovery of plasma present in and on thesurface of the conjunctiva can be used for a complete analysis of bloodcomponents. Plasma corresponds to the circulating chemistry of the bodyand it is the standard used in laboratories for sample testing.Interstitial fluid for instance is tested in labs only from corpses butnever from a living person.

Laboratories also do not use whole blood for measuring compounds such asfor example, glucose. Laboratories separate the plasma and then measurethe glucose present in plasma.

Measurement of glucose in whole blood is subject to many errors andinaccuracies. For example changes in hematocrit that occur particularlyin women, certain metabolic states, and in many diseases can have animportant effect on the true value of glucose levels. Moreover, thecellular component of blood alters the value of glucose levels.

Many of the machines which use whole blood (invasive means using fingerprick) give a fictitious value which attempts to indicate the plasmavalue. Measurements in interstitial fluid also give fictitious valueswhich tries to estimate what the plasma values of glucose would be ifmeasured in plasma.

Measurement of substances in the plasma gives the most accurate andprecise identification and concentration of said substances and reflectsthe true metabolic state of the body. In addition, the opticalproperties of plasma are stable and homogeneous in equivalent samplepopulation.

Evaluations have been made of the external surfaces and mucosal areas ofthe human body and only one area has been identified with superficialvessels and leakage of plasma. This area with fenestrations and plasmaleakage showed to be suitable for noninvasive measurements. Thispreferred area is the conjunctival lining of the eye including the tearpunctum lining.

Another area identified but with leakage of lymphatic fluid is in theoral mucosa between teeth, but leakage is of only a small amount, notconstant, and not coming from superficial vessels with fenestrations andplasma leakage as it occurs in the conjunctiva.

The methods and apparatus using superficially flowing plasma adjacent tothe conjunctiva as disclosed in the present invention provides anoptimal point for diagnostics and a point of maximum detected value andmaximum signal for determination of concentration or identification ofsubstances independent of the type of electromagnetic radiation beingdirected at or through the substance of interest in the sample.

These areas in the eye provide plasma already separated from thecellular component of blood with said plasma available superficially onthe surface of the eye and near the surface of the eye. The plasma fillsthe conjunctival interface in areas with blood vessels and without bloodvessels. Plasma flowing through fenestrations rapidly leaks andpermeates the whole conjunctival area, including areas denuded fromblood vessels.

The plasma can be used for non-invasive or minimally invasive analysis,for instance, using chemical, electrochemical, or microfluidic systems.The conjunctiva and plasma can also be used for evaluation andidentification of substances using electromagnetic means such as withthe optical techniques of the present invention. The measurementprovided by the present invention can determine the concentration of anyconstituent in the eye fluid located adjacent to the conjunctiva. Avariety of optical approaches such as infrared spectroscopy can be usedin the present invention to perform the measurements in the eyeincluding transmission, reflectance, scattering measurement, frequencydomain, or for example phase shift of modulated light transmittedthrough the substance of interest, or a combination of these.

The methods, apparatus, and systems of the present invention can usespectroscopic analysis of the eye fluid including plasma present on, in,or preferably under the conjunctiva to determine the concentration ofchemical species present in such eye fluid while removing or reducingall actual or potential sources of errors, sources of interference,variability, and artifacts.

The method and apparatus of the present invention overcomes all of theissues and problems associated with previous techniques and devices. Inaccordance with the present invention, plasma containing the substanceto be measured is already separated and can be used for measurementincluding simultaneous and continuous measurement of multiple substancespresent in said plasma or eye fluid. One of the approaches includesnon-invasive and minimally invasive means to optically measure thesubstance of interest located in the eye fluid adjacent to theconjunctiva.

An electromagnetic measurement, such as optical, is based on eye fluidincluding plasma flowing in a living being on the surface of the eye.The method and apparatus involves directing electromagnetic radiation ator through the conjunctiva with said radiation interacting with thesubstance of interest and being collected by a detector. The datacollected is then processed for obtaining a value indicative of theconcentration of the substance of interest.

It is very important to note that measurements using the electromagnetictechnique as described in the present invention do not require any flowof fluid to reach the sensor in order to determine the concentration ofthe substance of interest. The system is reagentless and determinationof the concentration of the substance of interest is accomplished simplyby detecting and analyzing radiation that interacts with the substanceof interest present adjacent to the conjunctiva The method and apparatusof the present invention include for example glucose measurement in thenear infrared wavelength region between 750 and 3000 nm and preferablyin the region where the highest absorption peaks are known to occur, forglucose for example in the region between 2080 to 2200 nm and forcholesterol centered around 2300 nm. The spectral region can alsoinclude infrared or visible wavelength to detect other chemicalsubstances besides glucose or cholesterol.

The apparatus includes at least one radiation source from infrared tovisible light which interacts with the substance of interest and iscollected by a detector. The number and value of the interrogationwavelengths from the radiation source depends upon the chemicalsubstance being measured and the degree of accuracy required. As thepresent invention provides reduction or elimination of sources ofinterference and errors, it is possible to reduce the number ofwavelengths without sacrificing accuracy. Previously, the mid-infraredregion has not been considered viable for measurement in humans becauseof the high water absorption that reduces penetration depths to microns.The present invention can use this mid-infrared region since the plasmawith the substance of interest is already separated and located verysuperficially and actually on the surface of the eye which allowssufficient penetration of radiation to measure said substance ofinterest.

The present invention reduces variability due to tissue structure,interfering constituents, and noise contribution to the signal of thesubstance of interest, ultimately substantially reducing the number ofvariables and the complexity of data analysis, either by empirical orphysical methods. The empirical methods including Partial Least squares(PLS), principal component analysis, artificial neural networks, and thelike while physical methods include chemometric techniques, mathematicalmodels, and the like. Furthermore, algorithms were developed usingin-vitro data which does not have extraneous tissue and interferingsubstances completely accounted for as occurs with measurement in deeptissues or with excess background noise such as in the skin and withblood in vivo. Conversely, standard algorithms for in-vitro testingcorrelates to the in vivo testing of the present invention since thestructures of the eye approximates a Lambertian surface and theconjunctiva is a transparent and homogeneous structure that can fit withthe light-transmission and light-scattering condition characterized byBeer-Lambert's law.

The enormous amount of interfering constituents, source of errors, andvariables in the sample which are eliminated or reduced with the presentinvention include:

-   -   Sample with various layers of tissue    -   Sample with scattering tissue    -   Sample with random thickness    -   Sample with unknown thickness    -   Sample-with different thickness among different individuals    -   Sample that changes in thickness with aging    -   Sample that changes in texture with aging    -   Sample with keratin    -   Sample that changes according to exposure to the environment    -   Sample with barriers to penetration of radiation    -   Sample that changes according to the local ambient    -   Sample with fat    -   Sample with cartilage    -   Sample with bone    -   Sample with muscle    -   Sample with high water content    -   Sample with walls of vessels    -   Sample with non-visible medium that is the source of the signal    -   Sample with opaque interface    -   Sample interface made out of dead tissue    -   Sample with interface that scars    -   Sample highly sensitive to pain and touch    -   Sample with melanin    -   Sample interface with different hue    -   Sample with hemoglobin    -   Sample medium which is in motion    -   Sample medium with cellular components    -   Sample with red blood cells    -   Sample with uneven distribution of the substance being measured    -   Sample with unsteady supply of the substance being measured    -   Non-homogeneous sample    -   Sample with low concentration of the substance being measured    -   Sample surrounded by structures with high-water content    -   Sample surrounded by irregular structures    -   Sample medium that pulsates    -   Sample with various and unknown thickness of vessel walls    -   Sample with unstable pressure    -   Sample with variable location    -   Sample filled with debris    -   Sample located deep in the body    -   Sample with unstable temperature    -   Sample with thermal gradient    -   Sample in no direct contact with thermal energy    -   Sample with no active heat transfer    -   Sample with heat loss    -   Sample influenced by external temperature    -   Sample with no-isothermic conditions    -   Sample with self-absorption of thermal energy

An exemplary representation of some of the interfering constituentspresent in the sample irradiated that are reduced or eliminated by thepresent invention.

-   a) Radiation directed at a target tissue can be absorbed by the    various constituents including several layers of the skin, various    blood cellular components, fat, bone, walls of the blood vessel, and    the like. This drastically reduces the signal and processing    requires subtracting all of those intervening elements. All of the    named interfering constituents in the sample irradiated are    eliminated with the present invention.-   b) Skin alone as the target tissue creates reduction of signal to    noise because skin by itself is an additional scattering tissue. The    present invention eliminates interfering scattering structures in    the sample irradiated.-   c) Thickness of the skin (which includes the surface of the tongue)    is random within the same individual even in an extremely small area    with changes in thickness depending on location. It is very    difficult to know the exact thickness of the skin from point to    point without histologic (tissue removal) studies. There is great    variability in signal due to skin thickness. All of those sources of    errors and variability such as random thickness and unknown    thickness of the structure in the sample irradiated are eliminated.-   d) Thickness of the skin also varies from individual to individual    at the exact same location in the skin and thus the signal has to be    individually considered for each living being. Individual variation    in thickness of the structure in the sample irradiated is also    eliminated.-   e) Changes in texture and thickness in the skin that occurs with    aging have a dramatic effect in acquiring accurate measurements.    Changes in texture and thickness due to aging of the structure in    the sample irradiated are also eliminated.-   f) Changes in the amount of keratin in the skin and tongue lining    which occurs in different metabolic and environmental conditions    also prevent accurate signal acquisition. Keratin and variability in    the sample irradiated are both also eliminated.-   g) Skin structure such as amount of elastin also varies greatly from    person to person, according to the amount of sun exposure,    pollution, changes in the ozone layer, and other environmental    factors which lead to great variability in signal acquisition. There    is elimination of the sample irradiated being susceptible to most of    the environmental factors by being naturally shielded from said    environmental factors.-   h) Due to the structure and thickness of the skin the radiation can    fail to penetrate and reach the location in which the substance of    interest is present. There is elimination of a structure in the    sample irradiated that can work as a barrier to radiation.-   i) Measurements are also affected by the day-to-day variations in    skin surface temperature and hydration in the same individual    according to ambient conditions and metabolic status of said    individual. There is elimination of structures in the sample    irradiated that is susceptible to changes in temperature and    hydration according to ambient conditions.-   j) The intensity of the reflected or transmitted signal can vary    drastically from patient to patient depending on the individual    physical characteristics such as the amount of fat. A thin and obese    person will vary greatly in the amount of fat and thus will vary    greatly in the radiation signal for the same concentration of the    substance of interest. There is elimination of fat in the sample    area being irradiated.-   k) The amount of protein such as muscle mass also varies greatly    from person to person. There is elimination of muscle mass    variability in the sample area being irradiated.-   l) The level of water content and hydration of skin and surrounding    structures varies from individual to individual and in the same    individual over time with evaporation. There is elimination of    variability from person to person and over time due to changes in    water evaporation in the sample area being irradiated.-   m) Thickness and texture of walls of blood vessels also change    substantially with aging and greatly vary from location to location.    There is elimination in the sample being irradiated of signal    variability due to presence of walls which change substantially with    aging and location.-   n) The deep blood vessels location and structure within the same age    group still varies greatly from person to person and anatomic    variation is fairly constant with different depth and location of    blood vessel in each individual. Since those blood vessels are    located deep and covered by an opaque structure like the skin it is    impossible to precisely determine the position of said blood    vessels. There is elimination of source medium for the signal which    is not visible during irradiation of the sample.

The use of conjunctiva and plasma present adjacent to said conjunctivaand the eyelid pocket provides an optimum location for measurement byelectromagnetic means in a stable environment which is undisturbed byinternal or external conditions.

Signal to noise is greatly improved since the thin transparentconjunctiva is the only intervening tissue in the optical path to betraversed from source to detector.

The conjunctiva does not age like the skin or blood vessels. Both thethickness and texture of the conjunctiva remain without major changesthroughout the lifespan of a person. That can be easily noted by lookingat the conjunctiva of a normal person but with different ages, such as a25 year old and a 65 year old person.

The conjunctiva is a well vascularized tissue, but still leaves most ofits area free from blood vessels which allows measurement of plasma tobe performed without interference by blood components. Those areas freeof vessels are easily identified and the eyeball of a normal person iswhite with few blood vessels. Furthermore, the conjunctiva in thecul-de-sac rim is free of blood vessels and plasma is collected theredue to gravity, and measurement of substance of interest in thecul-de-sac is one of the preferred embodiments of the present invention.

Moreover, the conjunctiva is capable of complete regeneration withoutscarring. Furthermore, the conjunctiva can provide easy coupling withthe surface of the sensing means since the conjunctiva surface is aliving tissue contrary to the skin surface and tongue lining which ismade out of dead tissue (keratin). In addition, the conjunctiva iseasily accessible manually or surgically. Besides, the conjunctiva hasonly a few pain fibers and no tactile fibers creating minimal sensationto touch and to any hardware in contact with the conjunctival tissue.

Skin has various layers with random and inconstant thickness. The skinhas several layers including: the epidermis which varies in thicknessdepending on the location from approximately 80 to 250 μ, the dermiswith thickness between approximately 1 to 2 mm, and the subcutaneoustissue which varies substantially in thickness according to area andphysical constitution of the subject and which falls in the centimeterrange reaching various centimeters in an obese person. The conjunctivais a few micrometers thick mono-layer structure with constant thicknessalong its entire structure. The thickness of the conjunctiva remains thesame regardless of the amount of body fat. Normal conjunctiva does nothave fat tissue.

In the present invention the superficial and the only interfaceradiated, involves the conjunctiva, a very thin layer of transparenthomogenous epithelial tissue. Wavelengths of less than 2000 nm do notpenetrate well through skin. Contrary to that, due to the structure andthickness of the conjunctiva, a broad range of wavelengths can be usedand will penetrate said conjunctiva.

Melanin is a cromophore and there is some amount of melanin in the skinof all normal individuals, with the exception of pathologic status as incomplete albinos. The skin with melanin absorbs near-infrared lightwhich is the spectral region of interest in near-infrared spectroscopyand the region, for example, where glucose absorbs light. The presentinvention eliminates surface barriers and sources of error andvariability such as melanin present in the skin and which varies fromsite to site and from individual to individual. Normal conjunctiva doesnot have melanin.

There are variations from person to person in thickness and color ofskin and texture of skin. Normal conjunctiva is transparent in allnormal individuals and has the equivalent thickness and texture.

The present invention eliminates enormous sample variability due tolocation as occur in the skin with different thickness and structureaccording to the area measured in said skin. The conjunctiva is a thinand homogeneous tissue across its entire surface area.

There is elimination of variability due to changes in texture andstructure as occur in the skin due to aging. The conjunctiva ishomogeneous and does not age like the skin. There is also elimination ofvariability found in the skin surface due to the random presence ofvarious glands such as sweat glands, hair follicles, and the like.

There is elimination of an optically-opaque structure like the skin. Itis very difficult to apply Beer-Lambert's law when using the skin. Thelaw describes the relationship between light absorption andconcentration and according to Beer-Lambert's law the absorbance of aconstituent is proportional to its concentration in solution. Theconjunctiva is a transparent and homogeneous structure which can fitwith the light-transmission and light-scattering phenomena characterizedby Beer-Lambert's law.

There is elimination of interfering constitutes and light scatteringelements such as fat, bone, cartilage and the like. The conjunctiva doesnot have a fat layer and radiation does not have to go through cartilageor bone to reach the substance of interest.

In the present invention the conjunctiva, which is a thin mono-layertransparent homogeneous structure, is the only interfering tissue beforeradiation reaches the substance of interest already separated andcollected in the plasma adjacent to said conjunctiva. Since theconjunctiva does not absorb the near-infrared light there is no surfacebarrier as an interfering constituent and since the conjunctiva is verythin and homogeneous there is minimal scattering after penetration.

In addition, the temperature in the eye is fairly constant and thepocket in the eyelid offers a natural and thermally sealed pocket forplacement of sensing means.

Presence of whole blood and other tissues such as skin scatters lightand further reduces the signal. The present invention eliminatesabsorption interference by cromophores such as hemoglobin such aspresent in whole blood. Radiation can be directed at the conjunctivalarea free of blood and hemoglobin, but with plasma collected underneath.Thus another source of error is eliminated as caused by confusion ofhemoglobin spectra with glucose spectra.

The reflective or transmissive measurements of the present inventioninvolve eye fluid and plasma adjacent to the conjunctiva which createsthe most homogeneous medium and provides signal to noise useful forclinical applications. The present invention provides plasma which isthe most accurate and precise medium for measuring and identifyingsubstances. The present invention provides said plasma covered only bythe conjunctiva which is a structure which does not absorb near-infraredlight.

The plasma is virtually static or in very slow motion as under theconjunctiva which creates a stable environment for measurement.

The plasma present in the eye provides a sample free of bloodconstituents which are source of errors and scattering. The plasma beingirradiated is free of major cellular components and it is homogeneouswith minimal scattering.

The background where the plasma is collected includes the sclera whichis a homogeneous and white reflective structure with virtually no watercontained in its layers. Thus, there is also elimination of surroundingtissue composed by large amounts of water.

The present invention eliminates light being radiated through a tissuewith varying amounts of glucose depending on the location such as theskin with the epidermis, dermis and subcutaneous having differentconcentrations of glucose. In the present invention glucose is evenlydistributed in the plasma adjacent to the conjunctiva.

The plasma present in the eye is a great source of undisturbed andstable signal for glucose as the eye requires a stable supply of glucosesince glucose is the only source of energy that can be used by theretina. The retina requires a steady supply of glucose for properfunctioning and to process visual information. The eye has a stablesupply of glucose and a relative increase in the amount of the substanceof interest such as for example glucose which increases the signal tonoise ratio and allows fewer wavelengths to be used in order to obtainmeasurements.

The eye also has the highest amount of blood per gram of tissue in thewhole body and thus provide a continuous supply of blood at high ratewhich is delivered as plasma through the conjunctival vessels.

The concentration of chemical substances in the plasma are high inrelation to the whole sample allowing a high signal to noise ratio to beacquired. Glucose is found in very dilute quantities in whole blood andinterstitial fluid but it is relatively concentrated in the plasmaproviding a higher signal as found in the surface of the eye. In complexmedia such as the blood where there is a great number of overlappingsubstances, the number of required wavelengths increases substantially.In a homogenous sample such as the plasma adjacent to the conjunctiva,the reduction in the number of wavelengths does not affect accuracy. Inaddition, it is difficult for a detector to identify the glucoseabsorption peak due to the variability in scatter as occurs with blood.The present invention can rely on more cost-effective detectors as theabsorption peak in the plasma sample can be more easily identified.

Due to the presence of minimal interfering components and high signal tonoise ratio, the present invention can detect lower glucose levels(hypoglycemia). The strength of signal for the substance of interest isa function of the concentration and the homogeneity of the sample. Bloodand other tissues are highly non-homogeneous. Contrary to that theplasma is highly homogeneous and with higher concentration of thesubstance of interest in relation to the total sample.

There is elimination of a very low signal source with great backgroundnoise as it occurs in the aqueous humor of the eye. Plasma generates ahigh signal due to the relative high concentration of the substance ofinterest already naturally separated from cellular components and withminimal background noise.

There is reduction in the amount of interfering elements such as water.The present invention includes water displacement both passively andactively. Passive displacement is observed when the concentration of thesubstance of interest increases as found in the plasma adjacent to theconjunctiva which decreases water interference and the sample issurrounded by the sclera which is a structure which does not containwater. Active displacement is observed when artificially using ahydrophobic surface for the contact device which displaces water fromthe surface of the tissue creating a dry interface.

There is elimination of structural and absorption backgroundirregularities as occur in the skin, inside of the eye, blood vessels,and the like. The conjunctiva is positioned against a smooth whitehomogeneous water-free surface, the sclera.

There is elimination of variability due to the direct pulsation of thewall of blood vessel. Blood by nature is constantly in rapid motion andsuch rapid motion can create significant variability in themeasurements. The present invention eliminates error and variability duerapid motion of the sample as occurs in blood vessels. Plasma flowscontinuously through fenestrations but not in a pulsatile manner. Theplasma collected adjacent to the conjunctiva has insignificant pulsatingcontent.

There is elimination of an important source of variability as occur inmoving blood with cellular components in a blood vessel which is nothomogeneous and creates further scattering. Plasma flows continuouslythrough fenestrations but without cellular components.

Many and rapid changes occur in flowing blood inside a blood vessel. Dueto this phenomena the resulting spectra has to be acquired in anextremely short period of time which is done in an attempt to decreasethe number of artifacts and source of errors. Due to the poor signalcreated by the various and rapid changes in flow, measurements have tobe repeated several times within a very short period of time and thetotal averaged. This leads to complicated construction of devices andcontrolling systems, but still only delivering a poor signal to noise.The present invention allows the spectra to be acquired over longerperiods of time and without the need for such repeat measurements sincethere is minimal background noise and interfering constituents. This,therefore, allows lower cost and more efficient systems to be made andused.

There are variations from person to person in thickness and texture ofblood vessel walls. There is also variability due to changes in textureand structure that occur in the vessel wall due to aging. The apparatusand methods of the present invention include directing radiation thatdoes not need to penetrate through the wall of blood vessels to acquirethe signal for the substance of interest. Therefore, the above source oferrors and variability are eliminated.

There is reduction or elimination of variability and error due tochanges in pressure between the sensor interface and the tissue. Manyerrors occur when techniques require placement of a body part againstthe sensor in which the subject or the operator is artificially applyingthe pressure. An example is when a subject applies his/her skin againstthe sensor or an operator grasps the tongue or finger of a subject. Thepressure applied by either the subject or the operator variessubstantially over time and from measurement to measurement and fromsubject to subject and from operator to operator. The interface betweenthe tissue and sensor changes continuously with contact pressure andmanipulation by the subject or operator since those structures such asskin and tongue have several layers that change and yield in reaction toapplied pressure. Even if pressure controlled systems are used, there issignificant variation because of the different texture and thicknessfrom individual to individual, from location to location, and in thesame individual over time which prevents precise measurements from beingacquired.

One of the preferred embodiments of the present invention which uses acontact device in the eyelid pocket eliminates this variation inpressure. The pressure applied by the eyelid in the resting state isfairly constant and equal in normal subjects with a horizontal force of25,000 dynes and a tangential force of 50 dynes. Furthermore, the otherembodiments which do not use a contact device in the eyelid pocket, canuse a probe resting on the surface of the tissue and also obtainaccurate measurements. Examples of those devices are slit-lamps whichcan be used for precise application of pressure against the surface ofthe eye and since the thickness and texture of the conjunctiva ishomogeneous, accurate and precise measurement can be obtained.

Depending on the amount and time of exposure, infrared radiationdirected at the tissue such as skin may prove uncomfortable and promoteunwanted heating and or damage to the surface irradiated. In the presentinvention the substance of interest is separated from most of thebackground noise and is located superficially and thus less radiationcan be used without affecting accuracy. The present invention enhancessignal to noise ratio without increasing the amount of radiation emittedand the increased risk of burning the surface being radiated.

Inconsistency in the location of the source and detector can be animportant source of error and variability. The eyelid pocket provides aconfined environment of fixed dimensions that provides a natural meansfor providing the consistency needed for accurate measurements. Inaddition, the measurements are much less sensitive to sensor locationsince the structure of the conjunctiva is homogeneous and the sensorsurface can rest and adhere to the conjunctival surface. The use of ahydrophobic surface in the contact device encasing the radiation sourceand detector means promotes adherence to the conjunctival surfacefurther allowing precise positioning.

The present invention also discloses minimally invasive techniques forplacement of systems under the conjunctiva that uses only one drop ofanesthetic for the procedure. The conjunctiva is the only superficialplace in the body that allows painless surgical implantation of hardwareto be done using simply one drop of anesthetic. Thus, the presentinvention eliminates the need for high-risk surgical procedures andinternal infection. In the minimally invasive embodiment, the deviceimplanted is located and implanted superficially and can be easilyremoved using just one drop of anesthetic.

Conjunctiva is transparent and thus the implant procedure can be doneunder direct view. The bulbar conjunctiva is not adherent to underlyingtissues and there is a natural space underneath said conjunctivaallowing easy view for placement and removal of an implantedsource/detector pair. Thus, there is elimination of the need tosurgically implant devices deep in the body such as around blood vesselsand inside the abdomen. There is elimination of implanting devicesblindly since the skin is not transparent. There is elimination of amajor surgical procedure in case of removal from inside the vessels,around the vessels, or inside the body.

In relation to the minimally invasive embodiment in which the opticalsensor system is placed under the conjunctiva, the present inventionprovides a sample, such as plasma, which is free from debris. In theminimally invasive embodiment of the present invention, the system ismeasuring glucose already separated and present in the plasma collectedadjacent to the sensor.

Body temperature such as is found in the surface of the skin is variableaccording to the environment and shift of spectra can occur with changesin temperature. The eyelid pocket provides an optimum location fortemperature measurement which has a stable temperature and which isundisturbed by the ambient conditions. The conjunctival area radiatedhas a stable temperature derived from the carotid artery. Moreover, whenthe embodiment uses a contact device which is located in the eyelidpocket, there is a natural, complete thermal seal and stable coretemperature. Good control of the temperature also provides increasedaccuracy and if desired, reduction of the number of wavelengths.Besides, the stable temperature environment allows use of the naturalbody infrared radiation emission as means to identify and measure thesubstance of interest.

Far-infrared radiation spectroscopy measures natural thermal emissionsafter said emissions interact and are absorbed by the substance ofinterest at the conjunctival surface. The present invention provides athermally stable medium, insignificant number of interferingconstituents, and the thin conjunctival lining is the only structure tobe traversed by the thermal emissions from the eye before reaching thedetector. Thus there is higher accuracy and precision when convertingthe thermal energy emitted as heat by the eye into concentration of thesubstance of interest.

The ideal thermal environment provided by the conjunctiva in the eyelidpocket can be used for non-invasive evaluation of blood componentsbesides the measurement of temperature. Far-infrared spectroscopy canmeasure absorption of far-infrared radiation contained in the naturalthermal emissions present in the eyelid pocket. Natural spectralemissions of infrared radiation by the conjunctiva and vessels includespectral information of blood components. The long wavelength emitted bythe surface of the eye as heat can be used as the source of infraredenergy that can be correlated with the identification and measurement ofthe concentration of the substance of interest. Infrared emissiontraverses only an extremely small distance from the eye surface to thesensor which means no attenuation by interfering constituents.

Spectral radiation of infrared energy from the surface of the eye cancorrespond to spectral information of the substance of interest. Thesethermal emissions irradiated as heat at 38 degrees Celsius can includethe 4,000 to 14,000 nm wavelength range. For example, glucose stronglyabsorbs light around the 9,400 nm band. When far-infrared heat radiationis emitted by the eye, glucose will absorb part of the radiationcorresponding to its band of absorption. Absorption of the thermalenergy by glucose bands is related in a linear fashion to blood glucoseconcentration in the thermally sealed and thermally stable environmentpresent in the eyelid pocket.

The natural spectral emission by the eye changes according to thepresence and concentration of a substance of interest. The far-infraredthermal radiation emitted follow Planck's Law and the predicted amountof thermal radiation can be calculated. Reference intensity iscalculated by measuring thermal energy absorption outside the substanceof interest band. The thermal energy absorption in the band of substanceof interest can be determined via spectroscopic means by comparing themeasured and predicted values at the conjunctiva/plasma interface. Thesignal is then converted to concentration of the substance of interestaccording to the amount of thermal energy absorbed.

The Intelligent Contact Lens in the eyelid pocket provides optimal meansfor non-invasive measurement of the substance of interest using naturalheat emission by the eye. Below is an exemplary representation ofvarious unique advantages and features provided by the presentinvention.

-   -   higher signal as found in the plasma/conjunctiva interface due        to less background interference    -   undisturbed signal since the heat source is in direct apposition        to the sensing means    -   stable temperature since the eyelid pocket is thermally sealed    -   the eyelid pocket functions as a cavity since the eyelid edge is        tightly opposed to the surface of the eyeball easily observed-in        the eye. To see the inside of the eyelid pocket it is necessary        to actively pull the eyelid.    -   there is no heat loss inside the cavity    -   there is active heat transfer from the vessels caused by local        blood flow in direct contact with the sensor    -   the temperature of the eye, by being supplied directly from the        central nervous system circulation, is in direct equilibrium        with core temperature.

Temperature is proportional to blood perfusion. The conjunctiva isextremely vascularized and the eye is the organ in the whole body withthe highest amount of blood per gram of tissue. The conjunctiva is athin homogeneous layer of equal composition and the eyelid pocket is asealed thermal environment without cooling of surface layers. The bloodvessels in the conjunctiva are branches of the carotid artery comingdirectly from the central nervous system which allows measuring theprecise core temperature of the body.

The eyelid pocket provides a sealed and homogeneous thermal environment.When the eyelids are closed (during blinking or with eyes closed) or atany time inside the eyelid pockets, the thermal environment of the eyeexclusively corresponds to the core temperature of the body. In theeyelid pocket there is prevention of passive heat loss in addition toassociated active heat transfer since the conjunctiva is a thin liningof tissue free of keratin and with capillary level on the surface.

Skin present throughout the body, including the tongue, is covered withkeratin, a dead layer of thick tissue that alters transmission ofinfrared energy emitted as heat. The conjunctiva does not have a keratinlayer and the sensor can be placed in intimate thermal contact with theblood vessels.

Skin with its various layers and other constituents selectively absorbinfrared energy emitted by deeper layers before said energy reaches thesurface of said skin. Contrary to that, the conjunctiva is homogeneouswith no absorption of infrared energy and the blood vessels are locatedon the surface. This allows undisturbed delivery of infrared energy tothe surface of the conjunctiva and to a temperature detector such as aninfrared detector placed in apposition to said surface of theconjunctiva.

In the skin and other superficial parts of the body there is a thermalgradient with the deeper layers being warmer than the superficiallayers. In the conjunctiva there is no thermal gradient since there isonly a mono-layer of tissue with vessels directly underneath. Thethermal energy generated by the conjunctival blood vessels exiting tothe surface corresponds to the undisturbed core temperature of the body.

The surface temperature of the skin and other body parts does notcorrespond to the blood temperature. The surface temperature in the eyecorresponds to the core temperature of the body.

Thus, skin is not suitable for creating a thermally sealed and stableenvironment for measuring temperature and the concentration of thesubstance of interest. Most important, no other part of the body, butthe eye provides a natural pocket structure for direct apposition of thetemperature sensor in direct contact with the surface of the bloodvessel. The conjunctiva and eyelid pocket provides a thermally sealedenvironment in which the temperature sensor is in direct apposition tothe heat source. Moreover, in the eyelid pocket thermal equilibrium isachieved immediately as soon as the sensor is placed in said eyelidpocket and in contact with the tissue surface.

The method and apparatus of the present invention provides optimal meansfor measurement of the concentration of the substance of interest fromthe infrared energy emissions by the conjunctival surface as well asevaluation of temperature with measurement of core temperature.

The temperature sensor, preferably a contact thermosensor, is positionedin the sealed environment provided by the eyelid pocket, whicheliminates spurious readings which can occur by accidental reading ofambient temperature.

The apparatus uses the steps of sensing the level of temperature,producing output electrical signals representative of the intensity ofthe radiation, converting the resulting input, and sending the convertedinput to a processor. The processor is adapted to provide the necessaryanalysis of the signal to determine the temperature and concentration ofthe substance of interest and displaying the temperature level and theconcentration of the substance of interest.

The apparatus can provide core temperature, undisturbed by theenvironment, and continuos measurement in addition to far-infraredspectroscopy analysis for determining the concentration of the substanceof interest with both single or continuous measurement.

The present invention includes means for directing preferablynear-infrared energy into the surface of the conjunctiva, means foranalyzing and converting the reflectance or back scattered spectrum intothe concentration of the substance of interest and means for positioningthe light source and detector means adjacent to the surface of the eye.The present invention also provides methods for determining theconcentration of a substance of interest with said methods including thesteps of using eye fluid including plasma present on, in, or below theconjunctiva,_directing electromagnetic radiation such as near-infraredat the plasma interface, detecting the near-infrared energy radiatedfrom said plasma interface, taking the resulting spectra and providingan electrical signal upon detection, processing the signal and reportingconcentration of the substance of interest according to said signal. Theinvention also includes means and methods for positioning the lightsources and detectors in stable position and with stable pressure andtemperature in relation to the surface to which radiation is directed toand received from. The plasma collected underneath the conjunctiva ispreferably used as the source medium for determination of theconcentration of the substance of interest.

The present invention further includes means for directing near-infraredenergy through the conjunctiva/plasma interface, means for positioningradiation source and detector diametrically opposed to each other, andmeans for analyzing and converting the transmitted resulting spectruminto the concentration of the substance of interest. The presentinvention also provides methods for determining the concentration of asubstance of interest with said methods including the steps of using eyefluid including plasma adjacent to the conjunctiva as the source mediumfor measuring the substance of interest, directing electromagneticradiation such as near-infrared through the conjunctiva/plasmainterface, collecting the near-infrared energy radiated from saidconjunctiva/plasma interface, taking the resulting spectra and providingan electrical signal upon detection, processing the signal and reportingconcentration of the substance of interest according to said signal. Theinvention also includes means and methods for positioning the radiationsources and detectors in a stable position and with stable pressure andtemperature in relation to the surface to which radiation is directedthrough.

The present invention yet includes means for collecting naturalfar-infrared radiation emitted as heat from the eye, means forpositioning a radiation collector to receive said radiation, and meansfor converting the collected radiation from the eye into theconcentration of the substance of interest. The present invention alsoprovides methods for determining the concentration of the substance ofinterest with said methods including the steps of using the naturalfar-infrared emission from the eye as the resulting radiation formeasuring the substance of interest, collecting the resulting radiationspectra in a thermally stable environment, providing an electricalsignal upon detection, processing the signal and reporting theconcentration of the substance of interest according to said signal. Athermally stable environment includes open eye or closed eye. Thethermal emission collection means are in contact with the conjunctiva inthe eyelid pocket with eyes open or closed.

With closed eye, the collection means can also be in contact with thecornea. With closed eyes the cornea is in equilibrium with the aqueoushumor inside the eye with transudation of fluid to the surface of thecornea. The cornea during closed eyes or blinking is in thermalequilibrium with core body temperature. When the eyes are closed theequilibrium created allows the evaluation of substances of interestusing a contact lens with optical or electrochemical sensors placed onthe surface of the cornea. The invention also includes means and methodsfor positioning the thermal emission collection means in a stableposition and with stable pressure and with eyes open or closed.

The present invention further includes measuring the core temperature ofthe body, both single and continuous measurements. The present inventionincludes means for collecting thermal radiation from the eye, means forpositioning temperature sensitive devices to receive thermal radiationfrom the eye in a thermally stable environment, and means for convertingsaid thermal radiation into the core temperature of the body. Thepresent invention also provides methods for determining core temperatureof the body with said methods including the steps of using thermalemissions from the eye in a thermally stable environment, collecting thethermal emission by the eye, providing an electrical signal upondetection, processing the signal and reporting the temperature level.The invention also includes means and methods for proper positioning ofthe temperature sensor in a stable position and with stable pressure asachieved in the eyelid pocket. The invention yet includes means tomonitor a bodily function and dispense medications or activate devicesaccording to the signal acquired. The invention further includesapparatus and methods for treating vascular abnormalities and cancer.The invention further includes means to dispense medications.

Substances of interest can include any substance present adjacent to theconjunctiva or surface of the eye which is capable of being analyzed byelectromagnetic means. For example but not by way of limitation suchsubstances can include any substance present in plasma such asmolecular, chemical or cellular, and for example exogenous chemicalssuch as drugs and alcohol as well as endogenous chemicals such asglucose, oxygen, bicarbonate, cardiac markers, cancer markers, hormones,glutamate, urea, fatty acids, cholesterol, triglycerides, proteins,creatinine, aminoacids and the like and cellular constituents such ascancer cells, and the like. Values such as pH can also be calculated aspH can be related to light absorption using reflectance spectroscopy.

Substances of interest can also include hemoglobin, cytochromes,cellular elements and metabolic changes corresponding to lightinteraction with said substances of interest when directingelectromagnetic radiation at said substances of interest. All of thoseconstituents and values can be optimally detected in the conjunctiva orsurface of the eye using electromagnetic means and in accordance withtheir optical, physical, and chemical characteristics.

For the purpose of the description herein, the sclera is considered asone structure. It is understood however, that the sclera has severallayers and surrounding structures including the episclera and Tenon'scapsule.

For the purpose of the description herein, light and radiation are usedinterchangeably and refers to a form of energy contained within theelectromagnetic spectrum.

The eye fluid, conjunctival area, methods and apparatus as disclosed bythe present invention provides ideal means and sources of signals formeasurement of any substance of interest allowing optimal and maximumsignals to be obtained. The present invention allows analyticalcalibration since the structure and physiology of the conjunctiva isstable and the amount of plasma collected adjacent to the conjunctiva isalso stable. This type of analytical calibration can be universal whichavoids clinical calibration that requires blood sampling individually asa reference.

The foregoing and other objects, features, aspects and advantages of thepresent invention will become more apparent from the following detaileddescription of the present invention when taken in conjunction with theaccompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic block diagram illustrating a system for measuringintraocular pressure in accordance with a preferred embodiment of thepresent invention.

FIGS. 2A-2D schematically illustrate a preferred embodiment of a contactdevice according the present invention.

FIG. 3 schematically illustrates a view seen by a patient when utilizingthe system illustrated in FIG. 1.

FIGS. 4 and 5 schematically depict multi-filter optical elements inaccordance with a preferred embodiment of the present invention.

FIGS. 5A-5F illustrate a preferred embodiment of an applicator forgently applying the contact device to the cornea in accordance with thepresent invention.

FIG. 6 illustrates an exemplary circuit for carrying out several aspectsof the embodiment illustrated in FIG. 1.

FIGS. 7A and 7B are block diagrams illustrating an arrangement capablecompensating for deviations in corneal thickness according to thepresent invention.

FIGS. 8A and 8B schematically illustrate a contact device utilizingbarcode technology in accordance with a preferred embodiment of thepresent invention.

FIGS. 9A and 9B schematically illustrate a contact device utilizingcolor detection technology in accordance with a preferred embodiment ofthe present invention.

FIG. 10 illustrates an alternative contact device in accordance with yetanother preferred embodiment of the present invention.

FIGS. 11A and 11B schematically illustrate an indentation distancedetection arrangement in accordance with a preferred embodiment of thepresent invention.

FIG. 12 is a cross-sectional view of an alternative contact device inaccordance with another preferred embodiment of the present invention.

FIGS. 13A-15 are cross-sectional views of alternative contact devices inaccordance with other embodiments of the present invention.

FIG. 16 schematically illustrates an alternative embodiment of thesystem for measuring intraocular pressure by applanation, according tothe present invention.

FIG. 16A is a graph depicting force (F) as a function of the distance(x) separating a movable central piece from the pole of a magneticactuation apparatus in accordance with the present invention.

FIG. 17 schematically illustrates an alternative optical alignmentsystem in accordance with the present invention.

FIGS. 18 and 19 schematically illustrate arrangements for guiding thepatient during alignment of his/her eye in the apparatus of the presentinvention.

FIGS. 20A and 20B schematically illustrate an alternative embodiment formeasuring intraocular pressure by indentation.

FIGS. 21 and 22 schematically illustrate embodiments of the presentinvention which facilitate placement of the contact device on the scleraof the eye.

FIG. 23 is a plan view of an alternative contact device which may beused to measure episcleral venous pressure in accordance with thepresent invention.

FIG. 24 is a cross-sectional view of the alternative contact devicewhich may be used to measure episcleral venous pressure in accordancewith the present invention.

FIG. 25 schematically illustrates an alternative embodiment of thepresent invention, which includes a contact device with a pressuretransducer mounted therein.

FIG. 25A is a cross-sectional view of the alternative embodimentillustrated in FIG. 25.

FIG. 26 is a cross-sectional view illustrating the pressure transducerof FIG. 25.

FIG. 27 schematically illustrates the alternative embodiment of FIG. 25when located in a patient's eye.

FIG. 28 illustrates an alternative embodiment wherein two pressuretransducers are utilized.

FIG. 29 illustrates an alternative embodiment utilizing a centrallydisposed pressure transducer.

FIG. 30 illustrates a preferred mounting of the alternative embodimentto eye glass frames.

FIG. 31 is a block diagram of a preferred circuit defined by thealternative embodiment illustrated in FIG. 25.

FIG. 32 is a schematic representation of a contact device situated onthe cornea of an eye with lateral extensions of the contact deviceextending into the sclera sack below the upper and lower eye lids andillustrating schematically the reception of a signal transmitted from atransmitter to a receiver and the processes performed on the transmittedsignal.

FIG. 33A is an enlarged view of the contact device shown in FIG. 32 withfurther enlarged portions of the contact device encircled in FIGS. 33Abeing shown in further detail in FIGS. 33B and 33C.

FIG. 34 is a schematic block diagram of a system of obtaining samplesignal measurements and transmitting and interpreting the results of thesample signals.

FIGS. 35A and 35C schematically represent the actuation of the contactdevice of the present invention by the opening and closing of the eyelids. FIG. 35B is an enlarged detail view of an area encircled in FIG.35A.

FIGS. 36A through 36J schematically illustrate various shapes of acontact device incorporating the principles of the present invention.

FIGS. 37A and 37B schematically illustrate interpretation of signalsgenerated from the contact device of the present invention and theanalysis of the signals to provide different test measurements andtransmission of this data to remote locations, such as an intensive careunit setting.

FIG. 38A schematically illustrates a contact device of the presentinvention with FIG. 38B being a sectional view taken along the sectionline shown in FIG. 38A.

FIG. 39A illustrates the continuous flow of fluid in the eye. FIG. 39Bschematically illustrates an alternative embodiment of the contactdevice of the present invention used under the eyelid to produce signalsbased upon flow of tear fluid through the eye and transmit the signalsby a wire connected to an external device.

FIG. 40A schematically illustrates an alternative embodiment of thepresent invention, used under the eye lid to produce signals indicativeof sensed glucose levels which are radio transmitted to a remote stationfollowed by communication through a publically available network.

FIG. 40B schematically illustrates an alternative embodiment of theglucose sensor to be used under the eyelid with signals transmittedthrough wires.

FIG. 41 illustrates an oversized contact device including a plurality ofsensors.

FIG. 42A illustrates open eye lids positioned over a contact deviceincluding a somnolence awareness device, whereas FIG. 42B illustratesthe closing of the eyelids and the production of a signal externallytransmitted to an alarm device.

FIG. 43 is a detailed view of a portion of an eyeball including a heatstimulation transmission device.

FIG. 44 is a front view of a heat stimulation transmission devicemounted on a contact device and activated by a remote hardware device.

FIG. 45 illustrates a band heat stimulation transmission device forexternal use or surgical implantation in any part of the body.

FIG. 46 illustrates a surgically implantable heat stimulationtransmission device for implantation in the eye between eye muscles.

FIG. 47 illustrates a heat stimulation device for surgical implantationin any part of the body.

FIG. 48 schematically illustrates the surgical implantation of anoverheating transmission device adjacent to a brain tumor.

FIG. 49 illustrates the surgical implantation of an overheatingtransmission device adjacent to a kidney tumor.

FIG. 50 illustrates an overheating transmission device and its variouscomponents.

FIG. 51 illustrates the surgical implantation of an overheatingtransmission devices adjacent to an intraocular tumor.

FIG. 52 schematically illustrates the surgical implantation of anoverheating transmission device adjacent to a lung tumor.

FIG. 53 schematically illustrates the positioning of an overheatingtransmission device adjacent to a breast tumor.

FIG. 54A is a side sectional view and FIG. 54B is a front view of acontact device used to detect chemical compounds in the aqueous humorlocated on the eye, with FIG. 54C being a side view thereof.

FIG. 55A schematically illustrates a microphone or motion sensor mountedon a contact device sensor positioned over the eye for detection ofheart pulsations or sound and transmission of a signal representative ofheart pulsations or sound to a remote alarm device with FIG. 55B beingan enlarged view of the alarm device encircled in FIG. 55A.

FIG. 56 illustrates a contact device with an ultrasonic dipolar sensor,power source and transmitter with the sensor located on the bloodvessels of the eye.

FIG. 57 schematically illustrates the location of a contact device witha sensor placed near an extraocular muscle.

FIG. 58A is a side sectional view illustrating a contact device having alight source for illumination of the back of the eye.

FIG. 58B illustrates schematically the transmission of light from alightsource for reflection off a blood vessel at the cup of the optic nerveand for receipt of the reflected light by a multioptical filter systemseparated from the reflecting surface by a predetermined distance andseparated from the light source by a predetermined distance forinterpretation of the measurement of the reflected light.

FIGS. 59A through 59C illustrate positioning of contact devices forneurostimulation of tissues in the eye and brain.

FIG. 60 is a schematic illustration of a contact device having a fixedfrequency transmitter and power source for being tracked by an orbitingsatellite.

FIG. 61 illustrates a contact device under an eyelid including apressure sensor incorporated in a circuit having a power source, an LEDdrive and an LED for production of an LED signal for remote activationof a device having a photodiode or optical receiver on a receptorscreen.

FIG. 62 is a cross-sectional view of a contact device having a drugdelivery system incorporated therein.

FIG. 63 schematically illustrates a block diagram of an artificialpancreas system.

FIG. 64A through 64D are schematic sectional illustrations ofexperiments performed on an eye.

FIGS. 65A through 65F shows a series of pictures related to in-vivotesting using fluorescein angiogram.

FIGS. 66A through 66C are schematic illustrations of an in-vivoangiogram according to the biological principles of the invention.

FIG. 67A is an exemplary schematic of the blood vessels in the skin,non-fenestrated.

FIG. 67B is an exemplary schmatic of the blood vessels in theconjunctiva, fenestrated.

FIG. 68A shows a photomicrograph of the junction between skin andconjunctiva.

FIG. 68B shows a schematic illustration of a cross section of the eyeshowing the location of the microscopic structure depicted in FIG. 68Aand associated structure in the eye.

FIGS. 69A and 69B show schematic illustrations of the dimensions andlocation of the conjunctiva.

FIG. 69C shows a schematic illustration of the vascularization of theconjunctiva and eye.

FIG. 69D is a photographic illustration of the palpebral and bulbarconjunctiva and blood vessels.

FIGS. 70A through 70C exemplary embodiments illustrating a continuousfeed-back system for non-invasive blood glucose monitoring.

FIG. 71 is a flow diagram showing the operational steps of the systemdepicted in FIG. 70A-70C.

FIGS. 72A and 72B are exemplary embodiments of the intelligent contactlens illustrating a complete microlaboratory of the current inventionusing microfluidics technology including power, control, processing andtransmission systems.

FIG. 73A through 73C are schematic illustrations of examples ofmicrofluidics systems according to the current invention.

FIGS. 74A through 74E are schematic illustrations of an exemplarybiosensor according to the principles of the current invention with theencircled area in FIG. 74A being shown on an enlarged scale in FIG. 74B.

FIGS. 75A through 75D are schematic illustrations of various designs forchemical membrane biosensors according to the principles of the currentinvention.

FIG. 76 is a schematic illustration of an exemplary embodiment with adual system in one single piece lens using both upper and lower eyelidpockets.

FIG. 77 is an exemplary embodiment in accordance with the principles ofthe invention.

FIGS. 78A through 78C are schematic illustrations of an exemplaryembodiment of dual system with two lenses using both upper and lowereyelid pockets with FIG. 78B being an enlarged view of the upper areaencircled in FIG. 78A and FIG. 78C being an enlarged view of the lowerarea encircled in FIG. 78A.

FIGS. 79A through 79C are schematic illustrations of exemplaryembodiments with transport enhancement capabilities.

FIG. 80 illustrates a microfluidic and bioelectronic chip system inaccordance with the present invention.

FIG. 81 is a schematic illustration of an integrated microfluidics andelectronics system in accordance with the present invention.

FIGS. 82A through 82D are schematic illustrations of an exemplaryembodiment for surgical implantation in the eye according to theprinciples of the current invention with FIG. 82C being an enlargedillustration of a portion of FIG. 82B.

FIG. 83 is a schematic illustration of an exemplary embodiment formeasurement of temperature and infectious agents according to theprinciples of the current invention.

FIG. 84 shows a schematic illustration of a dual system ICL with achemical sensing and a tracking device using global positioning systemtechnology.

FIG. 85 is a schematic block diagram of an apparatus according to onepreferred embodiment of the present invention.

FIG. 86 is a schematic diagram of a sensor in accordance to a preferredembodiment of FIG. 85.

FIG. 87 is a schematic block diagram of an apparatus according toanother preferred embodiment of the present invention.

FIG. 88 is a schematic representation of the frontal view of the surfaceof the eye FIGS. 89A-D illustrates different positions for the locationof sensor of FIG. 87.

FIG. 90 is a schematic block diagram of an apparatus according to apreferred embodiment of the present invention.

FIGS. 91A-C illustrates various sensing arrangements in accordance withthe embodiment of FIG. 90.

FIG. 92 schematically illustrates a preferred embodiment in accordancewith the embodiment of FIG. 90.

FIG. 93A schematically illustrates an alternative embodiment forimplantation.

FIG. 93B is an enlarged view of the sensor arrangement shown in FIG.93A.

FIG. 94 schematically illustrates another alternative embodiment of thepresent invention.

FIG. 95A schematically illustrates another embodiment of the presentinvention in cross-sectional view.

FIG. 95B is an enlarged view of the arrangement shown in FIG. 95A.

FIG. 96 schematically illustrates one preferred embodiment of thepresent invention.

FIG. 97A schematically illustrates one preferred embodiment of thepresent invention.

FIG. 97B is an enlarged view of the arrangement shown in FIG. 97A.

FIG. 97C schematically shows an alternative embodiment of the presentinvention.

FIG. 98A schematically illustrates a preferred embodiment forimplantation of the present invention.

FIG. 98B shows a cross-sectional view of the embodiment shown in FIG.98A.

FIGS. 99A-D schematically illustrates implantable sensors in accordancewith an alternative embodiment of the present invention.

FIG. 100A schematically illustrates the position of sensor in accordancewith a preferred embodiment of the present invention.

FIG. 100B shows an enlarged view of the sensor shown in FIG. 100A.

FIG. 100C is a schematic block diagram of an apparatus according to onepreferred embodiment of the present invention and shown schematically inFIGS. 100A-B.

FIG. 100D schematically illustrates a sensor arrangement in accordancewith a preferred embodiment of the present invention.

FIG. 101A is a schematic block diagram of an apparatus according to onepreferred embodiment of the present invention.

FIG. 101B shows a cross-sectional view of one preferred embodiment ofthe present invention in accordance with the embodiment of FIG. 101A.

FIGS. 102A-B shows a cross-sectional view of one preferred embodiment ofthe present invention.

FIG. 102C shows a cross-sectional view of an alternative embodiment ofthe present invention.

FIG. 103 schematically illustrates an alternative embodiment of thepresent invention.

FIG. 104A schematically illustrates a probe arrangement in accordancewith a preferred embodiment of the present invention.

FIG. 104B schematically illustrates a preferred embodiment of thepresent invention.

FIG. 104B(1-3) schematically illustrate various positions for directingthe probe arrangement in accordance with a preferred embodiment of thepresent invention.

FIG. 104C is a schematic block diagram for continuous monitoring ofchemical substances in accordance with a preferred embodiment of thepresent invention.

FIG. 104D is a schematic block diagram of a probe arrangement

FIG. 104E schematically illustrates a probe arrangement in accordancewith a preferred embodiment of the present invention.

FIGS. 104F-G shows cross-sectional views of the probe arrangement in twodifferent positions in relation to the tissue being evaluated.

FIGS. 104H-J shows a frontal view of different arrangements for thesensor and filter used in the measuring probe.

FIGS. 104K-1 shows a cross-sectional view of the probe arrangement usinga rotatable filter system in accordance with a preferred embodiment ofthe present invention.

FIGS. 104K-2 shows a frontal view of the rotatable filter of FIG.104K-1.

FIGS. 104L-N schematically illustrates various measuring arrangements inaccordance with an alternative embodiment of the present invention.

FIG. 104O schematically illustrates a probe arrangement with asupporting arm.

FIG. 104P schematically illustrates a probe arrangement for simultaneousnon-contact evaluation of both eyes for detection of abnormalities dueto asymmetric measurements.

FIG. 104Q, (1A), (1B), (2A), (2B), (3), (4) and (5) show a series ofpictures related to in-vivo evaluation of radiation of theconjunctiva/plasma interface using infrared imaging.

FIG. 105A is a schematic simplified block diagram of one preferredembodiment of the present invention.

FIG. 105B shows a waveform corresponding to heart rhythm achieved byusing a contact device and transducer placed on the eye.

FIG. 105C is a schematic block diagram of one preferred embodiment inaccordance to FIG. 105B.

FIG. 105(D-1) shows a cross-sectional view of a heating transmissiondevice adjacent to a neovascular membrane in the eye according to apreferred embodiment of the invention.

FIG. 105(D-2) shows a side view of the heating transmission device.

FIG. 105(D-3) shows a frontal view of the overheating transmissiondevice.

FIGS. 105(D-4 to D-6) schematically illustrates the surgicalimplantation of the device in FIG. 105(D-1).

FIG. 105(D-7) shows a frontal view of the overheating transmissiondevice in a cross-shape design.

FIG. 106A is a schematic illustration of a dispensation device inaccordance with a preferred embodiment of the present invention.

FIG. 106B is a schematic illustration of the preferred embodiment ofFIG. 106A with an attached handle.

FIGS. 107A-B is a cross sectional view of the embodiment of FIGS. 106A-Bbeing actuated by the eyelid.

FIG. 108 is a cross-sectional view of an alternative embodiment shown inFIGS. 107A-B.

FIG. 109 is a cross sectional view of one preferred embodiment of adispensation device.

FIGS. 110A-B schematically illustrates an alternative embodiment for thedispensation device.

DESCRIPTION OF THE PREFERRED EMBODIMENTS Applanation

A preferred embodiment of the present invention will now be describedwith reference to the drawings. According to the preferred embodimentillustrated in FIG. 1, a system is provided for measuring intraocularpressure by applanation. The system includes a contact device 2 forplacement in contact with the cornea 4, and an actuation apparatus 6 foractuating the contact device 2 so that a portion thereof projectsinwardly against the cornea 4 to provide a predetermined amount ofapplanation. The system further includes a detecting arrangement 8 fordetecting when the predetermined amount of applanation of the cornea 4has been achieved and a calculation unit 10 responsive to the detectingarrangement 8 for determining intraocular pressure based on the amountof force the contact device 2 must apply against the cornea 4 in orderto achieve the predetermined amount of applanation.

The contact device 2 illustrated in FIG. 1 has an exaggerated thicknessto more clearly distinguish it from the cornea 4. FIGS. 2A-2D moreaccurately illustrate a preferred embodiment of the contact device 2which includes a substantially rigid annular member 12, a flexiblemembrane 14 and a movable central piece 16. The substantially rigidannular member 12 includes an inner concave surface 18 shaped to matchan outer surface of the cornea 4 and having a hole 20 defined therein.The substantially rigid annular member 12 has a maximum thickness(preferably approximately 1 millimeter) at the hole 20 and aprogressively decreasing thickness toward a periphery 21 of thesubstantially rigid annular member 12. The diameter of the rigid annularmember is approximately 11 millimeters and the diameter of the hole 20is approximately 5.1 millimeters according to a preferred embodiment.Preferably, the substantially rigid annular member 12 is made oftransparent polymethylmethacrylate; however, it is understood that manyother materials, such as glass and appropriately rigid plastics andpolymers, may be used to make the annular member 12. Preferably, thematerials are chosen so as not to interfere with light directed at thecornea or reflected back therefrom.

The flexible membrane 14 is preferably secured to the inner concavesurface 18 of the substantially rigid annular member 12 to providecomfort for the wearer by preventing scratches or abrasions to thecorneal epithelial layer. The flexible membrane 14 is coextensive withat least the hole 20 in the annular member 12 and includes at least onetransparent area 22. Preferably, the transparent area 22 spans theentire flexible membrane 14, and the flexible membrane 14 is coextensivewith the entire inner concave surface 18 of the rigid annular member 12.According to a preferred arrangement, only the periphery of the flexiblemembrane 14 and the periphery of the rigid annular member 12 are securedto one another. This tends to minimize any resistance the flexiblemembrane might exert against displacement of the movable central piece16 toward the cornea 4.

According to an alternative arrangement, the flexible membrane 14 iscoextensive with the rigid annular member and is heat-sealed theretoover its entire extent except for a circular region within approximatelyone millimeter of the hole 20.

Although the flexible membrane 14 preferably consists of a soft and thinpolymer, such as transparent silicone elastic, transparent siliconrubber (used in conventional contact lens), transparent flexible acrylic(used in conventional intraocular lenses), transparent hydrogel, or thelike, it is-well understood that other materials may be used inmanufacturing the flexible membrane 14.

The movable central piece 16 is slidably disposed within the hole 20 andincludes a substantially flat inner side 24 secured to the flexiblemembrane 14. The engagement of the inner side 24 to the flexiblemembrane 14 is preferably provided by glue or thermo-contact techniques.It is understood, however, that various other techniques may be used inorder to securely engage the inner side 24 to the flexible membrane 14.Preferably, the movable central piece 16 has a diameter of approximately5.0 millimeters and a thickness of approximately 1 millimeter.

A substantially cylindrical wall 42 is defined circumferentially aroundthe hole 20 by virtue of the increased thickness of the rigid annularmember 12 at the periphery of the hole 20. The movable central piece 16is slidably disposed against this wall 42 in a piston-like manner andpreferably has a thickness which matches the height of the cylindricalwall 42. In use, the substantially flat inner side 24 flattens a portionof the cornea 4 upon actuation of the movable central piece 16 by theactuation apparatus 6.

The overall dimensions of the substantially rigid annular member 12, theflexible membrane 14 and the movable central piece 16 are determined bybalancing several factors, including the desired range of forces appliedto the cornea 4 during applanation, the discomfort tolerances of thepatients, the minimum desired area of applanation, and the requisitestability of the contact device 2 on the cornea 4. In addition, thedimensions of the movable central piece 16 are preferably selected sothat relative rotation between the movable central piece 16 and thesubstantially rigid annular member 12 is precluded, without hamperingthe aforementioned piston-like sliding.

The materials used to manufacture the contact device 2 are preferablyselected so as to minimize any interference with light incident upon thecornea 4 or reflected thereby.

Preferably, the actuation apparatus 6 illustrated in FIG. 1 actuates themovable central piece 16 to cause sliding of the movable central piece16 in the piston-like manner toward the cornea 4. In doing so, themovable central piece 16 and a central portion of the flexible membrane14 are caused to project inwardly against the cornea 4. This is shown inFIGS. 2C and 2D. A portion of the cornea 4 is thereby flattened.Actuation continues until a predetermined amount of applanation isachieved.

Preferably, the movable central piece 16 includes a magneticallyresponsive element 26 arranged so as to slide along with the movablecentral piece 1,6 in response to a magnetic field, and the actuationapparatus 6 includes a mechanism 28 for applying a magnetic fieldthereto. Although it is understood that the mechanism 28 for applyingthe magnetic field may include a selectively positioned bar magnet,according to a preferred embodiment, the mechanism 28 for applying themagnetic field includes a coil 30 of long wire wound in a closely packedhelix and circuitry 32 for producing an electrical current through thecoil 30 in a progressively increasing manner. By progressivelyincreasing the current, the magnetic field is progressively increased.The magnetic repulsion between the actuation apparatus 6 and the movablecentral piece 16 therefore increases progressively, and this, in turn,causes a progressively greater force to be applied against the cornea 4until the predetermined amount of applanation is achieved.

Using known principles of physics, it is understood that the electricalcurrent passing through the coil 30 will be proportional to the amountof force applied by the movable central piece 16 against the cornea 4via the flexible membrane 14. Since the amount of force required toachieve the predetermined amount of applanation is proportional tointraocular pressure, the amount of current required to achieve thepredetermined amount of applanation will also be proportional to theintraocular pressure. Thus, a conversion factor for converting a valueof current to a value of intraocular pressure can easily be determinedexperimentally upon dimensions of the system, the magneticresponsiveness of the magnetically responsive element 26, number of coilwindings, and the like.

Besides using experimentation techniques, the conversion factor may alsobe determined using known techniques for calibrating a tonometer. Suchknown techniques are based on a known relationship which exists betweenthe inward displacement of an indentation device and the volume changesand pressure in the indented eye. Examples of such techniques are setforth in Shiotz, Communications: Tonometry, The Brit. J. ofOphthalmology, June 1920, p. 249-266; Friedenwald, TonometerCalibration, Trans. Amer. Acad. of O. & O., January-February 1957, pp.108-126; and Moses, Theory and Calibration of the Schiotz Tonometer VII:Experimental Results of Tonometric Measurements: Scale Reading VersusIndentation Volume, Investigative Ophthalmology, September 1971, Vol.10, No. 9, pp. 716-723 .

In light of the relationship between current and intraocular pressure,the calculation unit 10 includes a memory 33 for storing a current valueindicative of the amount of current passing through the coil 30 when thepredetermined amount of applanation is achieved. The calculation unit 10also includes a conversion unit 34 for converting the current value intoan indication of intraocular pressure.

Preferably, the calculation unit 10 is responsive to the detectingarrangement 8 so that when the predetermined amount of applanation isachieved, the current value (corresponding to the amount of currentflowing through the coil 30) is immediately stored in the memory 33. Atthe same time, the calculation unit 10 produces an output signaldirecting the current producing circuitry 32 to terminate the flow ofcurrent. This, in turn, terminates the force against the cornea 4. In analternative embodiment, the current producing circuitry 32 could be madedirectly responsive to the detecting arrangement 8 (i.e., not throughthe calculation unit 10) so as to automatically terminate the flow ofcurrent through the coil 30 upon achieving the predetermined amount ofapplanation.

The current producing circuitry 32 may constitute any appropriatelyarranged circuit for achieving the progressively increasing current.However, a preferred current producing circuit 32 includes a switch anda DC power supply, the combination of which is capable of producing astep function. The preferred current producing circuitry 32 furthercomprises an integrating amplifier which integrates the step function toproduce the progressively increasing current.

The magnetically responsive element 26 is circumferentially surroundedby a transparent peripheral portion 36. The transparent peripheralportion 36 is aligned with the transparent area 22 and permits light topass through the contact device 2 to the cornea 4 and also permits lightto reflect from the cornea 4 back out of the contact device 2 throughthe transparent on peripheral portion 36. Although the transparentperipheral portion 36 may consist entirely of an air gap, for reasons ofaccuracy and to provide smoother sliding of the movable central piece 16through the rigid annular member 12, it is preferred that a transparentsolid material constitute the transparent peripheral portion 36.Exemplary transparent solid materials include polymethyl methacrylate,glass, hard acrylic, plastic polymers, and the like.

The magnetically responsive element 26 preferably comprises an annularmagnet having a central sight hole 38 through which a patient is able tosee while the contact device 2 is located on the patient's cornea 4. Thecentral sight hole 38 is aligned with the transparent area 22 of theflexible membrane 14 and is preferably at least 1-2 millimeters indiameter.

Although the preferred embodiment includes an annular magnet as themagnetically responsive element 26, it is understood that various othermagnetically responsive elements 26 may be used, including variousferromagnetic materials and/or suspensions of magnetically responsiveparticles in liquid. The magnetically responsive element 26 may alsoconsist of a plurality of small bar magnets arranged in a circle, tothereby define an opening equivalent to the illustrated central sighthole 38. A transparent magnet may also be used.

A display 40 is preferably provided for numerically displaying theintraocular pressure detected by the system. The display 40 preferablycomprises a liquid crystal display (LCD) or light emitting diode (LED)display connected and responsive to the conversion unit 34 of thecalculation unit 10.

Alternatively, the display 40 can be arranged so as to give indications,of whether the intraocular pressure is within certain ranges. In thisregard, the display 40 may include a green LED 40A, a yellow LED 40B,and a red LED 40C. When the pressure is within a predetermined highrange, the red LED 40C is illuminated to indicate that medical attentionis needed. When the intraocular pressure is within a normal range, thegreen LED 40A is illuminated. The yellow LED 40B is illuminated when thepressure is between the normal range and the high range to indicate thatthe pressure is somewhat elevated and that, although medical attentionis not currently needed, careful and frequent monitoring is recommended.

Preferably, since different patients may have different sensitivities orreactions to the same intraocular pressure, the ranges corresponding toeach LED 40A, 40B, 40C are calibrated for each patient by an attendingphysician. This way, patients who are more susceptible to consequencesfrom increased intraocular pressure may be alerted to seek medicalattention at a pressure less than the pressure at which otherless-susceptible patients are alerted to take the same action. The rangecalibrations maybe made using any known calibration device 40D includingvariable gain amplifiers or voltage divider networks with variableresistances.

The detecting arrangement 8 preferably comprises an optical detectionsystem including two primary beam emitters 44,46; two light sensors48,50; and two converging lenses 52,54. Any of a plurality ofcommercially available beam emitters may be used as emitters 44,46,including low-power laser beam emitting devices and infra-red (IR) beamemitting devices. Preferably, the device 2 and the primary beam emitters44,46 are arranged with respect to one another so that each of theprimary beam emitters 44,46 emits a primary beam of light toward thecornea through the transparent area 22 of the device and so that theprimary beam of light is reflected back through the device 2 by thecornea 4 to thereby produce reflected beams 60,62 of light with adirection of propagation dependent upon the amount of applanation of thecornea. The two light sensors 48,50 and two converging lenses 52,54 arepreferably arranged so as to be aligned with the reflected beams 60,62of light only when the predetermined amount of applanation of the cornea4 has been achieved. Preferably, the primary beams 56,58 pass throughthe substantially transparent peripheral portion 36.

Although FIG. 1 shows the reflected beams 60,62 of light diverging awayfrom one another and well away from the two converging lenses 52,54 andlight sensors 48,50, it is understood that as the cornea 4 becomesapplanated the reflected beams 60,62 will approach the two light sensors48,50 and the two converging lenses 52,54. When the predetermined amountof applanation is achieved, the reflected beams 60,62 will be directlyaligned with the converging lenses 52,54 and the sensors 48,50. Thesensors 48,50 are therefore able to detect when the predetermined amountof applanation is achieved by merely detecting the presence of thereflected beams 60,62. Preferably, the predetermined amount ofapplanation is deemed to exist when all of the sensors 48,50 receive arespective one of the reflected beams 60,62.

Although the illustrated arrangement is generally effective using twoprimary beam emitters 44,46 and two light sensors 48,50, better accuracycan be achieved in patients with astigmatisms by providing four beamemitters and four light sensors arranged orthogonally with respect toone another about the longitudinal axis of the actuation apparatus 6. Asin the case with two beam emitters 44,46 and light sensors 48,50, thepredetermined amount of applanation is preferably deemed to exist whenall of the sensors receive a respective one of the reflected beams.

A sighting arrangement is preferably provided for indicating when theactuation apparatus 6 and the detecting arrangement 8 are properlyaligned with the device 2. Preferably, the sighting arrangement includesthe central sight hole 38 in the movable central piece 16 through whicha patient is able to see while the device 2 is located on the patient'scornea 4. The central sight hole 38 is aligned with the transparent area22. In addition, the actuation apparatus 6 includes a tubular housing 64having a first end 66 for placement over an eye equipped with the device2 and a second opposite end 68 having at least one mark 70 arranged suchthat, when the patient looks through the central sight hole 38 at themark 70, the device 2 is properly aligned with the actuation apparatus 6and detecting arrangement 8.

Preferably, the second end 68 includes an internal mirror surface 72 andthe mark 70 generally comprises a set of cross-hairs. FIG. 3 illustratesthe view seen by a patient through the central sight hole 38 when thedevice 2 is properly aligned with the actuation apparatus 6 anddetecting arrangement 8. When proper alignment is achieved, thereflected image 74 of the central sight hole 38 appears in the mirrorsurface 72 at the intersection of the two cross-hairs which constitutethe mark 70. (The size of the image 74 is exaggerated in FIG. 3 to moreclearly distinguish it from other elements in the drawing).

Preferably, at least one light 75 is provided inside the tubular housing64 to illuminate the inside of the housing 64 and facilitatevisualization of the cross-hairs and the reflected image 74. Preferably,the internal mirror surface 72 acts as a mirror only when the light 75is on, and becomes mostly transparent upon deactivation of the light 75due to darkness inside the tubular housing 64. To that end, the secondend 68 of the tubular housing 68 maybe manufactured using “one-wayglass” which is often found in security and surveillance equipment.

Alternatively, if the device is to be used primarily by physicians,optometrists, or the like, the second end 68 may be merely transparent.If, on the other hand, the device is to be used by patients forself-monitoring, it is understood that the second end 68 may merelyinclude a mirror.

The system also preferably includes an optical distance measuringmechanism for indicating whether the device 2 is spaced at a properaxial distance from the actuation apparatus 6 and the detectingarrangement 8. The optical distance measurement mechanism is preferablyused in conjunction with the sighting arrangement.

Preferably, the optical distance measuring mechanism includes a distancemeasurement beam emitter 76 for emitting an optical distance measurementbeam 78 toward the device 2. The device 2 is capable of reflecting thedistance measurement beam 78 to produce a first reflected distancemeasurement beam 80. Arranged in the path of the first reflecteddistance measurement beam 80 is a preferably convex mirror 82. Theconvex mirror 82 reflects the first reflected distance measurement beam80 to create a second reflected distance measurement beam 84 and servesto amplify any variations in the first reflected beam's direction ofpropagation. The second reflected distance measurement beam 84 isdirected generally toward a distance measurement beam detector 86. Thedistance measurement beam detector 86 is arranged so that the secondreflected distance measurement beam 84 strikes a predetermined portionof the distance measurement beam detector 86 only when the device 2 islocated at the proper axial distance from the actuation apparatus 6 andthe detecting arrangement 8. When the proper axial distance is lacking,the second reflected distance measurement beam strikes another portionof the beam detector 86.

An indicator 88, such as an LCD or LED display, is preferably connectedand responsive to the beam detector 86 for indicating that the properaxial distance has been achieved only when the reflected distancemeasurement beam strikes the predetermined portion of the distancemeasurement beam detector.

Preferably, as illustrated in FIG. 1, the distance measurement beamdetector 86 includes a multi-filter optical element 90 arranged so as toreceive the second reflected distance measurement beam 84. Themulti-filter optical element 90 contains a plurality of optical filters92. Each of the optical filters 92 filters out a different percentage oflight, with the predetermined portion of the detector 86 being definedby a particular one of the optical filters 92 and a filtering percentageassociated therewith.

The distance measurement beam detector 86 further includes a beamintensity detection sensor 94 for detecting the intensity of the secondreflected distance measurement beam 84 after the beam 84 passes throughthe multi-filter optical element 90. Since the multi-filter opticalelement causes this intensity to vary with axial distance, the intensityis indicative of whether the device 2 is at the proper distance from theactuation apparatus 6 and the detecting arrangement 8.

A converging lens 96 is preferably located between the multi-filteroptical element 90 and the beam intensity detection sensor 94, forfocussing the second reflected distance measurement beam 84 on the beamintensity detection sensor 94 after the beam 84 passes through themulti-filter optical element 90.

Preferably, the indicator 88 is responsive to the beam intensitydetection sensor 94 so as to indicate what corrective action should betaken, when the device 2 is not at the proper axial distance from theactuation apparatus 6 and the detecting arrangement 8, in order toachieve the proper distance. The indication given by the indicator 88 isbased on the intensity and which of the plurality of optical filters 92achieves the particular intensity by virtue of a filtering percentageassociated therewith.

For example, when the device 2 is excessively far from the actuationapparatus 6, the second reflected distance measurement beam 84 passesthrough a dark one of the filters 92. There is consequently a reductionin beam intensity which causes the beam intensity detection sensor 94 todrive the indicator 88 with a signal indicative of the need to bring thedevice 2 closer to the actuation apparatus. The indicator 88 responds tothis signal by communicating the need to a user of the system.

Alternatively, the signal indicative of the need to bring the device 2closer to the actuation apparatus can be applied to a computer whichperforms corrections automatically.

In like manner, when the device 2 is excessively close to the actuationapparatus 6, the second reflected distance measurement beam 84 passesthrough a lighter one of the filters 92. There is consequently anincrease in beam intensity which causes the beam intensity detectionsensor 94 to drive the indicator 88 with a signal indicative of the needto move the device 2 farther from the actuation apparatus. The indicator88 responds to this signal by communicating the need to a user of thesystem.

In addition, computer-controlled movement of the actuation apparatusfarther away from the device 2 may be achieved automatically byproviding an appropriate computer-controlled moving mechanism responsiveto the signal indicative of the need to move the device 2 farther fromthe actuation apparatus.

With reference to FIG. 3, the indicator 88 preferably comprises threeLEDs arranged in a horizontal line across the second end 68 of thehousing 64. When illuminated, the left LED 88 a, which is preferablyyellow, indicates that the contact device 2 is too far from theactuation apparatus 6 and the detecting arrangement 8. Similarly, whenilluminated, the right LED 88 b, which is preferably red, indicates thatthe contact device 2 is too close to the actuation apparatus 6 and thedetecting arrangement 8. When the proper distance is achieved, thecentral LED 88 c is illuminated. Preferably, the central LED 88 c isgreen. The LEDs 88 a-88 c are selectively illuminated by the beamintensity detection sensor 94 in response to the beam's intensity.

Although FIG. 1 illustrates an arrangement of filters 92 wherein areduction in intensity signifies a need to move the device closer, it isunderstood that the present invention is not limited to such anarrangement. The multi-filter optical element 90, for example, may bereversed so that the darkest of the filters 92 is positioned adjacentthe end 68 of the tubular housing 64. When such an arrangement is used,an increase in beam intensity would signify a need to move the device 2farther away from the actuation apparatus 6.

Preferably, the actuation apparatus 6 (or at least the coil 30 thereof)is slidably mounted within the housing 64 and a knob and gearing (e.g.,rack and pinion) mechanism are provided for selectively moving theactuation apparatus 6 (or coil 30 thereof) axially through the housing64 in a perfectly linear manner until the appropriate axial distancefrom the contact device 2 is achieved. When such an arrangement isprovided, the first end 66 of the housing 64 serves as a positioningmechanism for the contact device 2 against which the patient presses thefacial area surrounding eye to be examined once the facial area restsagainst the first end 66, the knob and gearing mechanism are manipulatedto place the actuation apparatus 6 (or coil 30 thereof) at the properaxial distance from the contact device 2.

Although facial contact with the first end 66 enhances stability, it isunderstood that facial contact is not an essential step in utilizing thepresent invention.

The system also preferably includes an optical alignment mechanism forindicating whether the device 2 is properly aligned with the actuationapparatus 6 and the detecting arrangement 8. The optical alignmentmechanism includes two alignment beam detectors 48′, 50′ forrespectively detecting the reflected beams 60,62 of light prior to anyapplanation. The alignment beam detectors 48′, 50′ are arranged so thatthe reflected beams 60,62 of light respectively strike a predeterminedportion of the alignment beam detectors 48′, 50′ prior to applanationonly when the device 2 is properly aligned with respect to the actuationapparatus 6 and the detecting arrangement 8. When the device 2 is notproperly aligned, the reflected beams 60,62 strike another portion ofthe alignment beam detectors 48′, 50′, as will be described hereinafter.

The optical alignment mechanism further includes an indicatorarrangement responsive to the alignment beam detectors 48′, 50′. Theindicator arrangement preferably includes a set of LEDs 98,100,102,104which indicate that the proper alignment has been achieved only when thereflected beams 60,62 of light respectively strike the predeterminedportion of the alignment beam detectors 48′, 50′ prior to applanation.

Preferably, each of the alignment beam detectors 48′, 50′ includes arespective multi-filter optical element 106,108. The multi-filteroptical elements 106,108 are arranged so as to receive the reflectedbeams 60,62 of light. Each multi-filter optical element 106,108 containsa plurality of optical filters 110 ₁₀-110 ₉₀ (FIGS. 4 and 5), each ofwhich filters out a different percentage of light. In FIGS. 4 and 5, thedifferent percentages are labeled between 10 and 90 percent inincrements of ten percent. It is understood, however, that many otherarrangements and increments will suffice.

For the illustrated arrangement, it is preferred that the centrallylocated filters 110 ₅₀ which filter out 50% of the light represent thepredetermined portion of each alignment beam detector 48′, 50′. Properalignment is therefore deemed to exist when the reflected beams 60,62 oflight pass through the filters 110 ₅₀ and the intensity of the beams60,62 is reduced by 50%.

Each of the alignment beam detectors 48′, 50′ also preferably includes abeam intensity detector 112,114 for respectively detecting the intensityof the reflected beams 60,62 of light after the reflected beams 60,62 oflight pass through the multi-filter optical elements 106,108. Theintensity of each beam is indicative of whether the device 2 is properlyaligned with respect to the actuation apparatus 6 and the detectingarrangement.

A converging lens 116,118 is preferably located between eachmulti-filter optical element 106,108 and its respective beam intensitydetector 112,114. The converging lens 116,118 focusses the reflectedbeams 60,62 of light onto the beam intensity detectors 112,114 after thereflected beams 60,62 pass through the multi-filter optical elements106,108.

Each of the beam intensity detectors 112,114 has its output connected toan alignment beam detection circuit which, based on the respectiveoutputs from the beam intensity detectors 112,114, determines whetherthere is proper alignment, and if not, drives the appropriate one orones of the LEDs 98,100,102,104 to indicate the corrective action whichshould be taken.

As illustrated in FIG. 3, the LEDs 98,100,102,104 are respectivelyarranged above, to the right of, below, and to the left of theintersection of the cross-hairs 70. No LEDs 98,100,102,104 areilluminated unless there is a misalignment. Therefore, a lack ofillumination indicates that the device 2 is properly aligned with theactuation apparatus 6 and the detecting arrangement 8.

When the device 2 on the cornea 4 is too high, the beams 56,58 of lightstrike a lower portion of the cornea 4 and because of the cornea'scurvature, are reflected in a more downwardly direction. The reflectedbeams 60,62 therefore impinge on the lower half of the multi-filterelements 106,108, and the intensity of each reflected beam 60,62 isreduced by no more than 30%. The respective intensity reductions arethen communicated to the alignment detection circuit 120 by the beamintensity detectors 112,114. The alignment detection circuit 120interprets this reduction of intensity to result from a misalignmentwherein the device 2 is too high. The alignment detection circuit 120therefore causes the upper LED 98 to illuminate. Such illuminationindicates to the user that the device 2 is too high and must be loweredwith respect to the actuation apparatus 6 and the detecting arrangement8.

Similarly, when the device 2 on the cornea 4 is too low, the beams 56,58of light strike an upper portion of the cornea 4 and because of thecornea's curvature, are reflected in a more upwardly direction. Thereflected beams 60,62 therefore impinge on the upper half of themulti-filter elements 106,108, and the intensity of each reflected beam60,62 is reduced by at least 70%. The respective intensity reductionsare then communicated to the alignment detection circuit 120 by the beamintensity detectors 112,114. The alignment detection circuit 120interprets this particular reduction of intensity to result from amisalignment wherein the device 2 is too low. The alignment detectioncircuit 120 therefore causes the lower LED 102 to illuminate. Suchillumination indicates to the user that the device 2 is too low and mustbe raised with respect to the actuation apparatus 6 and the detectingarrangement 8.

With reference to FIG. 1, when the device 2 is too far to the right, thebeams 56,58 strike a more leftward side of the cornea 4 and because ofthe cornea's curvature, are reflected in a more leftward direction. Thereflected beams 60,62 therefore impinge on the left halves of themulti-filter elements 106,108. Since the filtering percentages decreasefrom left to right in multi-filter element 106 and increase from left toright in multifilter element 108, there will be a difference in theintensities detected by the beam intensity detectors 112,114. Inparticular, the beam intensity detector 112 will detect less intensitythan the beam intensity detector 114. The different intensities are thencommunicated to the alignment detection circuit 120 by the beamintensity detectors 112,114. The alignment detection circuit 120interprets the intensity difference wherein the intensity at the beamintensity detector 114 is higher than that at the beam intensitydetector 112, to result from a misalignment wherein the device 2 is toofar to the right in FIG. 1 (too far to the left in FIG. 3). Thealignment detection circuit 120 therefore causes the left LED 104 toilluminate. Such illumination indicates to the user that the device 2 istoo far to the left (in FIG. 3) and must be moved to the right (left inFIG. 1) with respect to the actuation apparatus 6 and the detectingarrangement 8.

Similarly, when the device 2 in FIG. 1 is too far to the left, the beams56,58 strike a more rightward side of the cornea 4 and because of thecornea's curvature, are reflected in a more rightwardly direction. Thereflected beams 60,62 therefore impinge on the right halves of themulti-filter elements 106,108. Since the filtering percentages decreasefrom left to right in multi-filter element 106 and increase from left toright in multifilter element 108, there will be a difference in theintensities detected by the beam intensity detectors 112,114. Inparticular, the beam intensity detector 112 will detect more intensitythan the beam intensity detector 114. The different intensities are thencommunicated to the alignment detection circuit 120 by the beamintensity detectors 112,114. The alignment detection circuit 120interprets the intensity difference wherein the intensity at the beamintensity detector 114 is lower than that at the beam intensity detector112, to result from a misalignment wherein the device 2 is too far tothe left in FIG. 1 (too far to the right in FIG. 3). The alignmentdetection circuit 120 therefore causes the right LED 100 to illuminate.Such illumination indicates to the user that the device 2 is too far tothe right (in FIG. 3) and must be moved to the left (right in FIG. 1)with respect to the actuation apparatus 6 and the detecting arrangement8.

The combination of LEDs 98,100,102,104 and the alignment detectioncircuit 120 therefore constitutes a display arrangement which isresponsive to the beam intensity detectors 112,114 and which indicateswhat corrective action should be taken, when the device 2 is notproperly aligned, in order to achieve proper alignment. Preferably, thesubstantially transparent peripheral portion 36 of the movable centralpiece 16 is wide enough to permit passage of the beams 56,58 to thecornea 4 even during misalignment.

It is understood that automatic alignment correction maybe provided viacomputer-controlled movement of the actuation apparatus upwardly,downwardly, to the right, and/or to the left, which computer-controlledmovement may be generated by an appropriate computer-controlled movingmechanism responsive to the optical alignment mechanism.

The optical alignment mechanism is preferably used in conjunction withthe sighting arrangement, so that the optical alignment mechanism merelyprovides indications of minor alignment corrections while the sightingarrangement provides an indication of major alignment corrections. It isunderstood, however, that the optical alignment mechanism can be used inlieu of the sighting mechanism if the substantially transparentperipheral portion 36 is made wide enough.

Although the foregoing alignment mechanism uses the same reflected beams60,62 used by the detecting arrangement 8, it is understood thatseparate alignment beam emitters may be used in order to provideseparate and distinct alignment beams. The foregoing arrangement ispreferred because it saves the need to provide additional emitters andthus is less expensive to manufacture.

Nevertheless, optional alignment beam emitters 122,124 are illustratedin FIG. 1. The alignment mechanism using these optional alignment beamemitters 122,124 would operate in essentially the same manner as itscounterpart which uses the reflected beams 60,62.

In particular, each of the alignment beam emitters 122,124 emits anoptical alignment beam toward the device 2. The alignment beam isreflected by the cornea 4 to produce a reflected alignment beam. Thealignment beam detectors 48′, 50′ are arranged so as to receive, not thereflected beams 60,62 of light, but rather the reflected alignment beamswhen the alignment beam emitters 122,124 are present. More specifically,the reflected alignment beams strike a predetermined portion of eachalignment beam detector 48′, 50′ prior to applanation only when thedevice 2 is properly aligned with respect to the actuation apparatus 6and the detecting arrangement 8. The rest of the system preferablyincludes the same components and operates in the same manner as thesystem which does not use the optional alignment beam emitters 122, 124.

The system may further include an applicator for gently placing thecontact device 2 on the cornea 4. As illustrated in FIGS. 5A-5F, apreferred embodiment of the applicator 127 includes an annular piece 127A at the tip of the applicator 127. The annular piece 127 A matches theshape of the movable central piece 16. Preferably, the applicator 127also includes a conduit 127CN having an open end which opens toward theannular piece 127A. An opposite end of the conduit 127CN is connected toa squeeze bulb 127SB. The squeeze bulb 127SB includes a one-way valve127V which permits the flow of air into the squeeze bulb 127SB, butprevents the flow of air out of the squeeze bulb 127SB through the valve127V. When the squeeze bulb 127SB is squeezed and then released, asuction effect is created at the open end of the conduit 127CN as thesqueeze bulb 127SB tries to expand to its pre-squeeze shape. Thissuction effect may be used to retain the contact device 2 at the tip ofthe applicator 127.

In addition, a pivoted lever system 127B is arranged to detach themovable central piece 16 from the annular piece 127A when a knob 127C atthe base of the applicator 127is pressed, thereby nudging the contactdevice 2 away from the annular piece 127A.

Alternatively, the tip of the applicator 127maybe selectively magnetizedand demagnetized using electric current flowing through the annularpiece 127A. This arrangement replaces the pivoted lever system 127B witha magnetization mechanism capable of providing a magnetic field whichrepels the movable central piece 16, thereby applying the contact device2 to the cornea 4.

A preferred circuit arrangement for implementing the above combinationof elements is illustrated schematically in FIG. 6. According to thepreferred circuit arrangement, the beam intensity detectors 112,114comprise a pair of photosensors which provide a voltage outputproportional to the detected beam intensity. The output from each beamintensity detector 112,114 is respectively connected to thenon-inverting input terminal of a filtering amplifier 126,128. Theinverting terminals of the filtering amplifiers 126,128 are connected toground. The amplifiers 126,128 therefore provide a filtering andamplification effect.

In order to determine whether proper vertical alignment exists, theoutput from the filtering amplifier 128 is applied to an inverting inputterminal of a vertical alignment comparator 130. The vertical alignmentcomparator 130 has its non-inverting input terminal connected to areference voltage Vref₁. The reference voltage Vref₁ is selected so thatit approximates the output from the filtering amplifier 128 whenever thelight beam 62 strikes the central row of filters 110 ₄₀₋₆₀ of themulti-filter optical element 108 (i.e., when the proper verticalalignment is achieved).

Consequently, the output from the comparator 130 is approximately zerowhen proper vertical alignment is achieved, is significantly negativewhen the contact device 2 is too high, and is significantly positivewhen the contact device 2 is too low. This output from the comparator130 is then applied to a vertical alignment switch 132. The verticalalignment switch 132 is logically arranged to provide a positive voltageto an AND-gate 134 only when the output from the comparator 130 isapproximately zero, to provide a positive voltage to the LED 98 onlywhen the output from the comparator 130 is negative, and to provide apositive voltage to the LED 102 only when the output from the comparator130 is positive. The LEDs 98,102 are thereby illuminated only when thereis a vertical misalignment and each illumination clearly indicates whatcorrective action should to be taken.

In order to determine whether proper horizontal alignment exists, theoutput from the filtering amplifier 126 is applied to a non-invertinginput terminal of a horizontal alignment comparator 136, while theinverting input terminal of the horizontal alignment comparator 136 isconnected to the output from the filtering amplifier 128. The comparator136 therefore produces an output which is proportional to the differencebetween the intensities detected by the beam intensity detectors112,114. This difference is zero whenever the light beams 60,62 strikethe central column of filters 110 ₂₀, 110 ₅₀, 110 ₈₀ of the multi-filteroptical elements 106,108 (i.e., when the proper horizontal alignment isachieved).

The output from the comparator 136 is therefore zero when the properhorizontal alignment is achieved, is negative when the contact device 2is too far to the right (in FIG. 1), and is positive when the contactdevice 2 is too far to the left (in FIG. 1). This output from thecomparator 130 is then applied to a horizontal alignment switch 138. Thehorizontal alignment switch 138 is logically arranged to provide apositive voltage to the AND-gate 134 only when the output from thecomparator 136 is zero, to provide a positive voltage to the LED 104only when the output from the comparator 136 is negative, and to providea positive voltage to the LED 100 only when the output from thecomparator 136 is positive. The LEDs 100, 104 are thereby illuminatedonly when there is a horizontal misalignment and each illuminationclearly indicates what corrective action should be taken.

In accordance with the preferred circuit arrangement illustrated in FIG.6, the beam intensity detection sensor 94 of the distance measurementbeam detector 86 includes a photosensor 140 which produces a voltageoutput proportional to the detected beam intensity. This voltage outputis applied to the non-inverting input terminal of a filtering amplifier142. The inverting terminal of the filtering amplifier 142 is connectedto ground. Accordingly, the filtering amplifier 142 filters andamplifies the voltage output from the photosensor 140. The output fromthe filtering amplifier 142 is applied to the non-inverting inputterminal of a distance measurement comparator 144. The comparator 144has its inverting terminal connected to a reference voltage Vref₂.Preferably, the reference voltage Vref₂ is selected so as to equal theoutput of the filtering amplifier 142 only when the proper axialdistance separates the contact device 2 from the actuation apparatus 6and detecting arrangement 8.

Consequently, the output from the comparator 144 is zero whenever theproper axial distance is achieved, is negative whenever the secondreflected beam 84 passes through a dark portion of the multi-filteroptical element 90 (i.e., whenever the axial distance is too great), andis positive whenever the second reflected beam 84 passes through a lightportion of the multifilter optical element 90 (i.e., whenever the axialdistance is too short).

The output from the comparator 144 is then applied to a distancemeasurement switch 146. The distance measurement switch 146 drives theLED 88 c with positive voltage whenever the output from the comparator144 is zero, drives the LED 88 b only when the output from thecomparator 144 is positive, and drives the LED 88 a only when the outputfrom the comparator 144 is negative. The LEDs 88 a, 88 b are therebyilluminated only when the axial distance separating the contact device 2from the actuation apparatus 6 and the detecting arrangement 8 isimproper. Each illumination clearly indicates what corrective actionshould be taken. Of course, when the LED 88 c is illuminated, nocorrective action is necessary.

With regard to the detecting arrangement 8, the preferred circuitarrangement illustrated in FIG. 6 includes the two light sensors 48,50.The outputs from the light sensors 48,50 are applied to and added by anadder 147. The output from the adder 147 is then applied to thenon-inverting input terminal of a filtering amplifier 148. The invertinginput terminal of the same amplifier 148 is connected to ground. As aresult, the filtering amplifier 148 filters and amplifies the sum of theoutput voltages from the light sensor 48,50. The output from thefiltering amplifier 148 is then applied to the non-inverting inputterminal of an applanation comparator 150. The inverting input terminalof the applanation comparator 150 is connected to a reference voltageVref₃. Preferably, the reference voltage Vref₃ is selected so as toequal the output from the filtering amplifier 148 only when thepredetermined amount of applanation is achieved (i.e., when thereflected beams 60,62 strike the light sensors 48,50). The output fromthe applanation comparator 150 therefore remains negative until thepredetermined amount of applanation is achieved.

The output from the applanation comparator 150 is connected to anapplanation switch 152. Th applanation switch 152 provides a positiveoutput voltage when the output from the applanation comparator 150 isnegative and terminates its positive output voltage whenever the outputfrom the applanation comparator 150 becomes positive.

Preferably, the output from the applanation switch 152 is connected toan applanation speaker 154 which audibly indicates when thepredetermined amount of applanation has been achieved. In particular,the speaker 154 is activated whenever the positive output voltage fromthe applanation, switch 152 initially disappears.

In the preferred circuit of FIG. 6, the coil 30 is electricallyconnected to the current producing circuitry 32 which, in turn, includesa signal generator capable of producing the progressively increasingcurrent in the coil 30. The current producing circuitry 32 is controlledby a start/stop switch 156 which is selectively activated anddeactivated by an AND-gate 158.

The AND-gate 158 has two inputs, both of which must exhibit positivevoltages in order to activate the start/stop switch 156 and currentproducing circuitry 32. A first input 160 of the two inputs is theoutput from the applanation switch 152. Since the applanation switch 152normally has a positive output voltage, the first input 160 remainspositive and the AND-gate is enabled at least with respect to the firstinput 160. However, whenever the predetermined amount of applanation isachieved (i.e. whenever the positive output voltage is no longer presentat the output from the applanation switch 152), the AND-gate 158deactivates the current producing circuitry 32 via the start/stop switch156.

The second input to the AND-gate 158 is the output from another AND-gate162. The other AND-gate 162 provides a positive output voltage only whena push-action switch 164 is pressed and only when the contact device 2is located at the proper axial distance from, and is properly alignedboth vertically and horizontally with, the actuation apparatus 6 and thedetecting arrangement 8. The current producing circuitry 32 thereforecannot be activated unless there is proper alignment and the properaxial distance has been achieved. In order to achieve such operation,the output from the AND-gate 134 is connected to a first input of theAND-gate 162 and the push-action switch 164 is connected to the secondinput of the AND-gate 162.

A delay element 163 is located electrically between the AND-gate 134 andthe AND-gate 162. The delay element 163 maintains a positive voltage atthe first input terminal to the AND-gate 162 for a predetermined periodof time after a positive voltage first appears at the output terminal ofthe AND-gate 134. The primary purpose of the delay element 163 is toprevent deactivation of the current producing circuitry 32 which wouldotherwise occur in response to changes in the propagation direction ofthe reflected beams 60,62 during the initial stages of applanation. Thepredetermined period of time is preferably selected pursuant to themaximum amount of time that it could take to achieve the predeterminedamount of applanation.

According to the preferred circuitry illustrated in FIG. 6, misalignmentand improper axial separation of the contact device 2 with respect tothe actuation apparatus 6 and detecting arrangement 8 is audiblyannounced by a speaker 166 and causes deactivation of a display 167. Thedisplay 167 and speaker 166 are connected and responsive to an AND-gate168. The AND-gate 168 has an inverting input connected to thepush-action switch 164 and another input connected to a three-inputOR-gate 170.

Therefore, when the push-action switch 164 is activated, the invertinginput terminal of the AND-gate 168 prevents a positive voltage fromappearing at the output from the AND-gate 168. Activation of the speaker166 is thereby precluded. However, when the push-action switch is notactivated, any positive voltage at any of the three inputs to theOR-gate 170 will activate the speaker 166. The three inputs to theOR-gate 170 are respectively connected to outputs from three otherOR-gates 172,174,176. The OR-gates 172,174,176, in turn, have theirinputs respectively connected to the LEDs 100,104, LEDs 98,102, and LEDs88 a, 88 b. Therefore, whenever any one of these LEDs 88 a, 88 b, 98,100, 102, 104 is activated, the OR-gate 170 produces a positive outputvoltage. The speaker 166, as a result, will be activated whenever anyone of the LEDs 88 a, 88 b, 98,100,102,104 is activated while thepush-action switch 164 remains deactivated.

Turning now to the current producing circuitry 32, the output from thecurrent producing circuitry 32 is connected to the coil 30. The coil 30,in turn, is connected to a current-to-voltage transducer 178. The outputvoltage from the current-to-voltage transducer 178 is proportional tothe current flowing through the coil 30 and is applied to thecalculation unit 10.

The calculation unit 10 receives the output voltage from the transducer178 and converts this output voltage indicative of current to an outputvoltage indicative of intraocular pressure. Initially, an output voltagefrom the filtering amplifier 142 indicative of the axial distanceseparating the contact device 2 from the actuation apparatus 6 and thedetecting arrangement 8, is multiplied by a reference voltage Vref₄using a multiplier 180. The reference voltage Vref₄ represents adistance calibration constant. The output from the multiplier 180 isthen squared by a multiplier 182 to create an output voltage indicativeof distance squared (d²).

The output from the multiplier 182 is then supplied to an input terminalof a divider 184. The other input terminal of the divider 184 receivesthe output voltage indicative of current from the current-to-voltagetransducer 178. The divider 184 therefore produces an output voltageindicative of the current in the coil 30 divided by the distance squared(I/d²);

The output voltage from the divider 184 is then applied to a multiplier186. The multiplier 186 multiplies the output voltage from the divider184 by a reference voltage Vref₅. The reference voltage Vref₅corresponds to a conversion factor for converting the value of (I/d²) toa value indicative of force in Newtons being applied by the movablecentral piece 16 against the cornea 4. The output voltage from themultiplier 186 is therefore indicative of the force in Newtons beingapplied by the movable central piece 16 against the cornea.

Next, the output voltage from the multiplier 186 is applied to an inputterminal of a divider 188. The other input terminal of the divider 188receives a reference voltage Vref₆. The reference voltage Vref₆corresponds to a calibration constant for converting force (in Newtons)to pressure (in Pascals) depending on the surface area of the movablecentral piece's substantially flat inner side 24. The output voltagefrom the divider 188 is therefore indicative of the pressure (inPascals) being exerted by the cornea 4 against the inner side of themovable central piece 16 in response to displacement of the movablecentral piece 16.

Since the pressure exerted by the cornea 4 depends upon the surface areaof the substantially flat inner side 24, the output voltage from thedivider 188 is indicative of intraocular pressure only when the cornea 4is being applanated by the entire surface area of the inner side 24.This, in turn, corresponds to the predetermined amount of applanation.

Preferably, the output voltage indicative of intraocular pressure isapplied to an input terminal of a multiplier 190. The multiplier 190 hasanother input terminal connected to a reference voltage Vref₇. Thereference voltage Vref₇ corresponds to a conversion factor forconverting pressure in Pascals to pressure in millimeters of mercury(mmHg). The voltage output from the multiplier 190 therefore isindicative of intraocular pressure in millimeters of mercury (mmHg)whenever the predetermined amount of applanation is achieved.

The output voltage from the multiplier 190 is then applied to thedisplay 167 which provides a visual display of intraocular pressurebased on this output voltage. Preferably, the display 167 or calculationunit 10 includes a memory-device 33 which stores a pressure valueassociated with the output voltage from the multiplier 190 whenever thepredetermined amount of applanation is achieved. Since the currentproducing circuitry 32 is automatically and immediately deactivated uponachieving the predetermined amount of applanation, the intraocularpressure corresponds to the pressure value associated with the peakoutput voltage from the multiplier 190. The memory therefore can betriggered to store the highest pressure value upon detecting a drop inthe output voltage from the multiplier 190. Preferably, the memory isautomatically reset prior to any subsequent measurements of intraocularpressure.

Although FIG. 6 shows the display 167 in digital form, it is understoodthat the display 167 may have any known form. The display 167 may alsoinclude the three LEDs 40A, 40B, 40C illustrated in FIG. 1 which give avisual indication of pressure ranges which, in turn, are calibrated foreach patient.

As indicated above, the illustrated calculation unit 10 includesseparate and distinct multipliers 180,182,186,190 and dividers 184,188for converting the output voltage indicative of current into an outputvoltage indicative of intraocular pressure in millimeters of mercury(mmHg). The separate and distinct multipliers and dividers arepreferably provided so that variations in the system's characteristicscan be compensated for by appropriately changing the reference voltagesVref₄, Vref₅, Vref₆ and/or Vref₇. It is understood, however, that whenall of the system's characteristics remain the same (e.g., the surfacearea of the inner side 24 and the desired distance separating thecontact device 2 from the actuation apparatus 6 and detectingarrangement 8) and the conversion factors do not change, that a singleconversion factor derived from the combination of each of the otherconversion factors can be used along with a single multiplier or dividerto achieve the results provided by the various multipliers and dividersshown in FIG. 6.

Although the above combination of elements is generally effective ataccurately measuring intraocular pressure in a substantial majority ofpatients, some patients have unusually thin or unusually thick corneas.This, in turn, may cause slight deviations in the measured intraocularpressure. In order to compensate for such deviations, the circuitry ofFIG. 6 may also include a variable gain amplifier 191 (illustrated inFIG. 7A) connected to the output from the multiplier 190. For themajority of patients, the variable gain amplifier 191 is adjusted toprovide a gain (g) of one. The variable gain amplifier 191 thereforewould have essentially no effect on the output from the multiplier 190.

However, for patients with unusually thick corneas, the gain (g) isadjusted to a positive gain less than one. A gain (g) of less than oneis used because unusually thick corneas are more resistant toapplanation and consequently result in a pressure indication thatexceeds, albeit by a small amount, the actual intraocular pressure. Theadjustable gain amplifier 191 therefore reduces the output voltage fromthe multiplier 190 by a selected percentage proportional to the cornea'sdeviation from normal corneal thickness.

For patients with unusually thin corneas, the opposite effect would beobserved. Accordingly, for those patients, the gain (g) is adjusted to apositive gain greater than one so that the adjustable gain amplifier 191increases the output voltage from the multiplier 190 by a selectedpercentage proportional to the cornea's deviation from normal cornealthickness.

Preferably, the gain (g) is manually selected for each patient using anyknown means for controlling the gain of a variable gain amplifier, forexample, a potentiometer connected to a voltage source. As indicatedabove, the particular gain (g) used depends on the thickness of eachpatient's cornea which, in turn, can be determined using known cornealpachymetry techniques. Once the corneal thickness is determined, thedeviation from the normal thickness is calculated and the gain (g) isset accordingly.

Alternatively, as illustrated in FIG. 7B, the gain (g) may be selectedautomatically by connecting an output (indicative of corneal thickness)from a known pachymetry apparatus 193 to a buffer circuit 195. Thebuffer circuit 195 converts the detected corneal thickness to a gainsignal associated with the detected thickness' deviation from the normalcorneal thickness. In particular, the gain signal produces a gain (g) ofone when the deviation is zero, produces a gain (g) greater than onewhen the detected corneal thickness is less than the normal thickness,and produces a gain (g) less than one when the detected cornealthickness is greater than the normal thickness.

Although FIGS. 7A and 7B illustrate a configuration which compensatesonly for corneal thickness, it is understood that similar configurationscan be used to compensate for corneal curvature, eye size, ocularrigidity, and the like. For levels of corneal curvature which are higherthan normal, the gain would be less than one. The gain would be greaterthan one for levels of corneal curvature which are flatter than normal.Typically, each increase in one diopter of corneal curvature isassociated with a 0.34 mm Hg increase in pressure. The intraocularpressure rises 1 mm Hg for very 3 diopters. The gain therefore can beapplied in accordance with this general relationship.

In the case of eye size compensation, larger than normal eyes wouldrequire a gain which is less than one, while smaller than normal eyeswould require a gain which is greater than one.

For patients with “stiffer” than normal ocular rigidities, the gain isless than one, but for patients with softer ocular rigidities, the gainis greater than one.

As when compensating for corneal thickness, the gain may be manuallyselected for each patient, or alternatively, the gain may be selectedautomatically by connecting the apparatus of the present invention to aknown keratometer when compensating for corneal curvature, and/or aknown biometer when compensating for eye size.

Despite not being illustrated, it is understood that the system includesa power supply mechanism for selectively powering the system usingeither batteries or household AC current.

Operation of the preferred circuitry will now be described. Initially,the contact device 2 is mounted on the corneal surface of a patient andtends to locate itself centrally at the front of the cornea 4 inessentially the same way as conventional contact lenses. The patientthen looks through the central sight hole 38 at the intersection of thecross-hairs which define the mark 70, preferably, while the light 75provided inside the tubular housing 64 is illuminated to facilitatevisualization of the cross-hairs and the reflected image 74. A roughalignment is thereby achieved.

Next, the preferred circuitry provides indications of misalignment orimproper axial distance should either or both exist. The patientresponds to such indications by taking the indicated corrective action.

Once proper alignment is achieved and the proper axial distance existsbetween the actuation apparatus 6 and the contact device 2, push-actionswitch 164 is activated and the AND-gate 158 and start/stop switch 156activate the current producing circuitry 32. In response to activation,the current producing circuitry 32 generates the progressivelyincreasing current in the coil 30. The progressively increasing currentcreates a progressively increasing magnetic field in the coil 30. Theprogressively increasing magnetic field, in turn, causes axialdisplacement of the movable central piece 16 toward the cornea 4 byvirtue of the magnetic field's repulsive effect on the magneticallyresponsive element 26. Since axial displacement of the movable centralpiece 16 produces a progressively increasing applanation of the cornea4, the reflected beams 60,62 begin to swing angularly toward the lightsensors 48,50. Such axial displacement and increasing applanationcontinues until both reflected beams 60,62 reach the light sensors 48,50and the predetermined amount of applanation is thereby deemed to exist.At that instant, the current producing circuit 32 is deactivated by theinput 160 to AND-gate 158; the speaker 154 is momentarily activated togive an audible indication that applanation has been achieved; and theintraocular pressure is stored in the memory device 33 and is displayedon display 167.

Although the above-described and illustrated embodiment includes variouspreferred elements, it is understood that the present invention may beachieved using various other individual elements. For example, thedetecting arrangement 8 may utilize various other elements, includingelements which are typically utilized in the art of barcode reading.

With reference to FIGS. 8A and 8B, a contact device 2′ maybe providedwith a barcode-like pattern 300 which varies in response to displacementof the movable central piece 16′. FIG. 8A illustrates the preferredpattern 300 prior to displacement of the movable central piece 16′; andFIG. 8B shows the preferred pattern 300 when the predetermined amount ofapplanation is achieved. The detecting arrangement therefore wouldinclude a barcode reader directed generally toward the contact device 2′and capable of detecting the differences in the barcode pattern 300.

Alternatively, as illustrated in FIGS. 9A and 9E, the contact device 2′maybe provided with a multi-color pattern 310 which varies in responseto displacement of the movable central piece 16′. FIG. 9A schematicallyillustrates the preferred color pattern 310 prior to displacement of themovable central piece 16′, while FIG. 9B schematically shows thepreferred pattern 310 when the predetermined amount of applanation isachieved. The detecting arrangement therefore would include a beamemitter for emitting a beam of light toward the pattern 310 and adetector which receives a reflected beam from the pattern 310 anddetects the reflected color to determine whether applanation has beenachieved.

Yet another way to detect the displacement of the movable central piece16 is by using a two dimensional array photosensor that senses thelocation of a reflected beam of light. Capacitive and electrostaticsensors, as well as changes in magnetic field can then be used to encodethe position of the reflected beam and thus the displacement of themovable central piece 16.

According to yet another alternative embodiment illustrated in FIG. 10,a miniature LED 320 is inserted into the contact device 2′. Thepiezoelectric ceramic is driven by ultrasonic waves or is alternativelypowered by electromagnetic waves. The brightness of the miniature LED320 is determined by the current flowing through the miniature LED 320which, in turn, may be modulated by a variable resistance 330. Themotion of the movable central piece 16′ varies the variable resistance330. Accordingly, the intensity of light from the miniature LED 320indicates the magnitude of the movable central piece's displacement. Aminiature, low-voltage primary battery 340 may be inserted into, thecontact device 2′ for powering the miniature LED 320.

With regard to yet another preferred embodiment of the presentinvention, it is understood that a tear film typically covers the eyeand that a surface tension resulting therefrom may cause underestimationof the intraocular pressure. Accordingly, the contact device of thepresent invention preferably has an inner surface of hydrophobicflexible material in order to decrease or eliminate this potentialsource of error.

It should be noted that the drawings are merely schematicrepresentations of the preferred embodiments. Therefore, the actualdimensions of the preferred embodiments and physical arrangement of thevarious elements is not limited to that which is illustrated. Variousarrangements and dimensions will become readily apparent to those ofordinary skill in the art. The size of the movable central piece, forexample, can be modified for use in animals or experimental techniques.Likewise, the contact device can be made with smaller dimensions for usewith infants and patients with eye lid abnormalities.

One preferred arrangement of the present invention includes a handleportion extending out from below the housing 64 and connected distallyto a platform. The platform acts as, a base for placement on a planarsurface (e.g., a table), with the handle projecting up therefrom tosupport the actuation apparatus 6 above the planar surface.

Indentation

The contact device 2 and associated system illustrated in FIGS. 1-5 mayalso be used to detect intraocular pressure by indentation. Whenindentation techniques are used in measuring intraocular pressure, apredetermined force is applied against the cornea using an indentationdevice. Because of the force, the indentation device travels in towardthe cornea, indenting the cornea as it travels. The distance travelledby the indentation device into the cornea in response to thepredetermined force is known to be inversely proportional to intraocularpressure. Accordingly, there are various known tables which, for certainstandard sizes of indentation devices and standard forces, correlate thedistance travelled and intraocular pressure.

In utilizing the illustrated arrangement for indentation, the movablecentral piece 16 of the contact device 2 functions as the indentationdevice. In addition, the current producing circuit 32 is switched tooperate in an indentation mode. When switched to the indentation mode,the current producing circuit 32 supplies a predetermined amount ofcurrent through the coil 30. The predetermined amount of currentcorresponds to the amount of current needed to produce one of theaforementioned standard forces.

The predetermined amount of current creates a magnetic field in theactuation apparatus 6. This magnetic field, in turn, causes the movablecentral piece 16 to push inwardly against the cornea 4 via the flexiblemembrane 14. Once the predetermined amount of current has been appliedand a standard force presses against the cornea, it is necessary todetermine how far the movable central piece 16 moved into the cornea 4.

Accordingly, when measurement of intraocular pressure by indentation isdesired, the system illustrated in FIG. 1 further includes a distancedetection arrangement for detecting a distance travelled by the movablecentral piece 16, and a computation portion 199 in the calculation unit10 for determining intraocular pressure based on the distance travelledby the movable central piece 16 in applying the predetermined amount offorce.

A preferred indentation distance detection arrangement 200 isillustrated in FIGS. 11A and 11B and preferably includes a beam emitter202 and a beam sensor 204. Preferably, lenses 205 are disposed in theoptical path between the beam emitter 202 and beam sensor 204. The beamemitter 202 is arranged so as to emit a beam 206 of light toward themovable central piece 16. The beam 206 of light is reflected back fromthe movable central piece 16 to create a reflected beam 208. The beamsensor 204 is positioned so as to receive the reflected beam 208whenever the device 2 is located at the proper axial distance and inproper alignment with the actuation apparatus 6. Preferably, the properdistance and alignment are achieved using all or any combination of theaforementioned sighting mechanism, optical alignment mechanism andoptical distance measuring mechanism.

Once proper alignment and the proper axial distance are achieved, thebeam 206 strikes a first portion of the movable central piece 16, asillustrated in FIG. 11A. Upon reflection of the beam 206, the reflectedbeam 208 strikes a first portion of the beam sensor 204. In FIG. 11A,the first portion is located on the beam sensor 204 toward the rightside of the drawing.

However, as indentation progresses, the movable central piece 16 becomesmore distant from the beam emitter 202. This increase in distance isillustrated in FIG. 11A. Since the movable central piece 16 moveslinearly away, the beam 206 strikes progressively more to the left onthe movable central piece 16. The reflected beam 206 therefore shiftstoward the left and strikes 204 at a second portion which is to the leftof the first portion.

The beam sensor 204 is arranged so as to detect the shift in thereflected beam 206, which shift is proportional to the displacement ofthe movable central piece 16. Preferably, the beam sensor 204 includesan intensity responsive beam detector 212 which produces an outputvoltage proportional to the detected intensity of the reflected beam 208and an optical filter element 210 which progressively filters more lightas the light's point of incidence moves from one portion of the filterto an opposite portion.

In FIGS. 11A and 11B, the optical filter element 210 comprises a filterwith a progressively increasing thickness so that light passing througha thicker portion has a more significantly reduced intensity than lightpassing through a thinner portion of the filter. Alternatively, thefilter can have a constant thickness and progressively increasingfiltering density whereby a progressively increasing filtering effect isachieved as the point of incidence moves across a longitudinal length ofthe filter.

When, as illustrated in FIG. 11A, the reflected beam 208 passes througha thinnest portion of the optical filter element 210 (e.g., prior toindentation), the reflected beam's intensity is reduced by only a smallamount. The intensity responsive beam detector 212 therefore provides arelatively high output voltage indicating that no movement of themovable central piece 16 toward the cornea 4 has occurred.

However, as indentation progresses, the reflected beam 208 progressivelyshifts toward thicker portions of the optical filter element 210 whichfilter more light. The intensity of the reflected beam 208 thereforedecreases proportionally to the displacement of the movable centralpiece 16 toward the cornea 4. Since the intensity responsive beamdetector 212 produces an output voltage proportional to the reflectedbeam's intensity, this output voltage decreases progressively as thedisplacement of the movable central piece 16 increases. The outputvoltage from the intensity responsive beam detector 212 is thereforeindicative of the movable central piece's displacement.

Preferably, the computation portion 199 is responsive to the currentproducing circuitry 32 so that, once the predetermined amount of forceis applied, the output voltage from the beam detectors 212 is receivedby the computation portion 199. The computation portion then, based onthe displacement associated with the particular output voltage,determines intraocular pressure. Preferably, the memory 33 includes amemory location for storing a value indicative of the intraocularpressure.

Also, the computation portion 199 preferably has access to anelectronically or magnetically stored one of the aforementioned knowntables. Since the tables indicate which intraocular pressure correspondswith certain distances traveled by the movable central piece 16, thecomputation portion 199 is able to determine intraocular pressure bymerely determining which pressure corresponds with the distance traveledby the movable central piece 16.

The system of the present invention may also be used to calculate therigidity of the sclera. In particular, the system is first used todetermine intraocular pressure by applanation and then is used todetermine intraocular pressure by indentation. The differences betweenthe intraocular pressures detected by the two methods would then beindicative of the sclera's rigidity.

Although the foregoing description of the preferred systems generallyrefers to a combined system capable of detecting intraocular pressure byboth applanation and indentation, it is understood that a combinedsystem need not be created. That is, the system capable of determiningintraocular pressure by applanation may be constructed independentlyfrom a separate system for determining intraocular pressure byindentation and vice versa.

Measuring Hydrodynamics of the Eye

The indentation device of the present invention may also be utilized tonon-invasively measure hydrodynamics of an eye including outflowfacility. The method of the present invention preferably comprisesseveral steps including the following:

According to a first step, an indentation device is placed in contactwith the cornea. Preferably, the indentation device comprises thecontact device 2 illustrated in FIGS. 1 and 2A-2D.

Next, at least one movable portion of the indentation device is moved intoward the cornea using a first predetermined amount of force to achieveindentation of the cornea. When the indentation device is the contactdevice 2, the movable portion consists of the movable central piece 16.

An intraocular pressure is then determined based on a first distancetraveled toward the cornea by the movable portion of the indentationdevice during application of the first predetermined amount of force.Preferably, the intraocular pressure is determined using theaforementioned system for determining intraocular pressure byindentation.

Next, the movable portion of the indentation device is rapidlyreciprocated in toward the cornea and away from the cornea at a firstpredetermined frequency and using a second predetermined amount of forceduring movement toward the cornea to thereby force intraocular fluid outfrom the eye. The second predetermined amount of force is preferablyequal to or greater than the first predetermined amount of force. It isunderstood, however, that the second predetermined amount of force maybe less than the first predetermined amount of force. The reciprocation,which preferably continues for 5 seconds, should generally not exceed 10seconds induration.

The movable portion is then moved in toward the cornea using a thirdpredetermined amount of force to again achieve indentation of thecornea.

A second intraocular pressure is then determined based on a seconddistance traveled toward the cornea by the movable portion of theindentation device during application of the third predetermined amountof force. This second intraocular pressure is also preferably determinedusing the aforementioned system for determining intraocular pressure byindentation. Since intraocular pressure decreases as a result of forcingintraocular fluid out of the eye during the rapid reciprocation of themovable portion, it is generally understood that, unless the eye is sodefective that no fluid flows out therefrom, the second intraocularpressure will be less than the first intraocular pressure. Thisreduction in intraocular pressure is indicative of outflow facility.

Next, the movable portion of the indentation device is again rapidlyreciprocated in toward the cornea and away from the cornea, but at asecond predetermined frequency and using a fourth predetermined amountof force during movement toward the cornea. The fourth predeterminedamount of force is preferably equal or greater than the secondpredetermined amount of force. It is understood, however, that thefourth predetermined amount of force may be less than the secondpredetermined amount of force. Additional intraocular fluid is therebyforced out from the eye. This reciprocation, which also preferablycontinues for 5 seconds, should generally not exceed 10 seconds induration.

The movable portion is subsequently moved in toward the cornea using afifth predetermined amount of force to again achieve indentation of thecornea.

Thereafter, a third intraocular pressure is determined based on a thirddistance traveled toward the cornea by the movable portion of theindentation device during application of the fifth predetermined amountof force.

The differences are then preferably calculated between the first,second, and third distances, which differences are indicative of thevolume of intraocular fluid which left the eye and therefore are alsoindicative of the outflow facility. It is understood that the differencebetween the first and last distances may be used, and in this regard, itis not necessary to use the differences between all three distances. Infact, the difference between any two of the distances will suffice.

Although the relationship between the outflow facility and the detecteddifferences varies when the various parameters of the method and thedimensions of the indentation device change, the relationship for givenparameters and dimensions can be easily determined by known experimentaltechniques and/or using known Friedenwald Tables.

The method of the present invention is preferably carried out using anindenting surface which is three millimeters in diameter and a computerequipped with a data acquisition board. In particular, the computergenerates the predetermined forces via a digital-to-analog (D/A)converter connected to the current generating circuitry 32. The computerthen receives signals indicative of the first, second, and thirdpredetermined distances via an analog-to-digital (AID) converter. Thesesignals are analyzed by the computer using the aforementionedrelationship between the differences in distance and the outflowfacility. Based on this analysis, the computer creates an output signalindicative of outflow facility. The output signal is preferably appliedto a display screen which, in turn, provides a visual indication ofoutflow facility.

Preferably, the method further comprises the steps of plotting thedifferences between the, first, second, and third distances to a createa graph of the differences and comparing the resulting graph ofdifferences to that of a normal eye to determine if any irregularitiesin outflow facility are present. As indicated above, however, it isunderstood that the difference between the first and last distances maybe used, and in this regard, it is not necessary to use the differencesbetween all three distances. In fact, the difference between any two ofthe distances will suffice.

Preferably, the first predetermined frequency and second predeterminedfrequency are substantially equal and are approximately 20 Hertz.Generally, any frequencies up to 35 Hertz can be used, thoughfrequencies below 1 Hertz are generally less desirable because thestress relaxation of the eye's outer coats would contribute to changesin pressure and volume.

The fourth predetermined amount of force is preferably at least twicethe second predetermined amount of force, and the third predeterminedamount of force is preferably approximately half of the firstpredetermined amount of force. It is understood, however, that otherrelationships will suffice and that the present method is not limited tothe foregoing preferred relationships.

According to a preferred use of the method, the first predeterminedamount of force is between 0.01 Newton and 0.015 Newton; the secondpredetermined amount of force is between 0.005 Newton and 0.0075 Newton;the third predetermined amount of force is between 0.005 Newton and0.0075 Newton; the fourth predetermined amount of force is between0.0075 Newton and 0.0125 Newton; the fifth predetermined amount of forceis between 0.0125 Newton and 0.025 Newton; the first predeterminedfrequency is between 1 Hertz and 35 Hertz; and the second predeterminedfrequency is also between 1 Hertz and 35 Hertz. The present method,however, is not limited to the foregoing preferred ranges.

Although the method of the present invention is preferably carried outusing the aforementioned device, it is understood that various othertonometers may be used. The method of the present invention therefore isnot limited in scope to its use in conjunction with the claimed systemand illustrated contact device.

Alternative Embodiments of the Contact Device

Although the foregoing description utilizes an embodiment of the contactdevice 2 which includes a flexible membrane 14 on the inside surface ofthe contact device 2, it is readily understood that the presentinvention is not limited to such an arrangement. Indeed, there are manyvariations of the contact device which fall well within the scope of thepresent invention.

The contact device 2, for example, may be manufactured with no flexiblemembrane, with the flexible membrane on the outside surface of thecontact device 2 (i.e., the side away from the cornea), with theflexible membrane on the inside surface of the contact device 2, or withthe flexible membrane on both sides of the contact device 2.

Also, the flexible membrane (s) 14 can be made to have an annular shape,thus permitting light to pass undistorted directly to the movablecentral piece 16 and the cornea for reflection thereby.

In addition, as illustrated in FIG. 12, the movable central piece 16 maybe formed with a similar annular shape so that a transparent centralportion thereof merely contains air. This way, light passing through theentire contact device 2 impinges directly on the cornea withoutundergoing any distortion due to the contact device 2.

Alternatively, the transparent central portion can be filled with atransparent solid material. Examples of such transparent solid materialsinclude polymethyl methacrylate, glass, hard acrylic, plastic polymers,and the like. According to a preferred arrangement, glass having anindex of refraction substantially greater than that of the cornea isutilized to enhance reflection of light by the cornea when the lightpasses through the contact device 2. Preferably, the index of refractionfor the glass is greater than 1.7, compared to the typical index ofrefraction of 1.37 associated with the cornea.

It is understood that the outer surface of the movable central piece 16may be coated with an anti-reflection layer in order to eliminateextraneous reflections from that surface which might otherwise interferewith operation of the alignment mechanism and the applanation detectingarrangement.

The interconnections of the various components of the contact device 2are also subject to modification without departing from the scope andspirit of the present invention. It is understood therefore that manyways exist for interconnecting or otherwise maintaining the workingrelationship between the movable central piece 16, the rigid annularmember 12, and the membranes 14.

When one or two flexible membranes 14 are used, for example, thesubstantially rigid annular member 12 can be attached to any one or bothof the flexible membrane(s) 14 using any known attachment techniques,such as gluing, heat-bonding, and the like. Alternatively, when twoflexible membranes 14 are used, the components maybe interconnected orotherwise maintained in a working relationship, without having todirectly attach the flexible membrane 14 to the substantially rigidannular member 12. Instead, the substantially rigid annular member 12may be retained between the two flexible membranes 14 by bonding themembranes to one another about their peripheries while the rigid annularmember 12 is sandwiched between the membranes 14.

Although the-movable central piece 16 maybe attached to the flexiblemembrane(s) 14 by gluing, heat-bonding, and the like, it is understoodthat such attachment is not necessary. Instead, one or both of theflexible membranes 14 can be arranged so as to completely or partiallyblock the movable central piece 16 and prevent it from falling out ofthe hole in the substantially rigid annular member 12. When theaforementioned annular version of the flexible membranes 14 is used, asillustrated by way of example in FIG. 12, the diameter of the hole in atleast one of the annular flexible membranes 14 is preferably smallerthan that of the hole in the substantially rigid annular member 12 sothat a radially inner portion 14A of the annular flexible membrane 14overlaps with the movable central piece 16 and thereby prevents themovable central piece 16 from falling out of the hole in thesubstantially rigid annular member 12.

As illustrated in FIG. 13A, another way of keeping the movable centralpiece 16 from falling out of the hole in the substantially rigid annularmember 12 is to provide arms 16A which extend radially out from themovable central piece 16 and are slidably received in respective grooves16B. The grooves 16B are formed in the rigid annular member 12. Eachgroove 16B has a longitudinal dimension (vertical in FIG. 13) which isselectively chosen to restrict the range of movement of the movablecentral piece 16 to within predetermined limits. Although FIG. 13 showsan embodiment wherein the grooves are in the substantially rigid annularmember 12 and the arms extend out from the movable central piece 16, itis understood that an equally effective arrangement can be created byreversing the configuration such that the grooves are located in themovable central piece 16 and the arms extend radially in from thesubstantially rigid annular member 12.

Preferably, the grooves 16B include resilient elements, such asminiature springs, which bias the position of the movable central piece16 toward a desired starting position. In addition, the arms 16A mayinclude distally located miniature wheels which significantly reduce thefriction between the arms 16A and the walls of the grooves 16B.

FIG. 13B illustrates another way of keeping the movable central piece 16from falling out of the hole in the substantially rigid annular member12. In FIG. 13B, the substantially rigid annular member 12 is providedwith radially inwardly extending flaps 12F at the outer surface of theannular member 12. One of the aforementioned annular membranes 14 ispreferably disposed on the inner side of the substantially rigid annularmember 12. Preferably, a portion of the membrane 14 extends radiallyinwardly past the walls of the rigid annular member's hole. Thecombination of the annular membrane 14 and the flaps 12F keeps themovable central piece 16 from falling out of the hole in thesubstantially rigid annular member 12.

The flaps 12F may also be used to achieve or facilitate actuation of themovable central piece 16. In a magnetically actuated embodiment, forexample, the flaps 12F may be magnetized so that the flaps 12F moveinwardly in response to an externally applied magnetic field.

With reference to FIG. 14, an alternative embodiment of the contactdevice 2 is made using a soft contact lens material 12A having aprogressively decreasing thickness toward its outer circumference. Acylindrical hole 12B is formed in the soft contact lens material 12A.The hole 12B, however, does not extend entirely through the soft contactlens material 12A. Instead, the hole has a closed bottom defined by athin portion 12C of the soft contact lens material 12A. The movablecentral piece 16 is disposed slidably within the hole 12B, andpreferably, the thin portion 12C is no more than 0.2 millimeters thick,thereby allowing the movable central piece 16 to achieve applanation orindentation when moved against the closed bottom of the hole toward thecornea with very little interference from the thin portion 12C.

Preferably, a substantially rigid annular member 12D is inserted andsecured to the soft contact material 12A to define a more stable wallstructure circumferentially around the hole 12B. This, in turn, providesmore stability when the movable central piece 16 moves in the hole 12B.

Although the soft lens material 12A preferably comprises Hydrogel,silicone, flexible acrylic, or the like, it is understood that any othersuitable materials may be used. In addition; as indicated above, anycombination of flexible membranes may be added to the embodiment of FIG.14. Although the movable central piece 16 in FIG. 14 is illustrated asbeing annular, it is understood that any other shape may be utilized.For example, any of the previously described movable central pieces 16would suffice.

Similarly, the annular version of the movable central piece 16 may bemodified by adding a transparent bottom plate (not illustrated) whichdefines a flat transparent bottom surface of the movable central piece16. When modified in this manner, the movable central piece 16 wouldhave a generally cup-shaped appearance. Preferably, the flat transparentbottom surface is positioned toward the cornea to enhance the flatteningeffect of the movable central piece 16; however, it is understood thatthe transparent plate can be located on the outside surface of themovable central piece 16 if desired.

Although the movable central piece 16 and the hole in the substantiallyrigid annular member 12 (or the hole in the soft contact lens material12A) are illustrated as having complementary cylindrical shapes, it isunderstood that the complementary shapes are not limited to a cylinder,but rather can include any shape which permits sliding of the movablecentral piece 16 with respect to its surrounding structure.

It is also understood that the movable central piece 16 may be mounteddirectly onto the surface of a flexible membrane 14 without using asubstantially rigid annular member 12. Although such an arrangementdefines a working embodiment of the contact device 2, its stability,accuracy, and level of comfort are significantly reduced compared tothat of a similar embodiment utilizing the substantially rigid annularmember 12 with a progressively tapering periphery.

Although the illustrated embodiments of the movable central piece 16include generally flat outside surfaces with well defined lateral edges,it is understood that the present invention is not limited to sucharrangements. The present invention, for example, can include a movablecentral piece 16 with a rounded outer surface to enhance comfort and/orto coincide with the curvature of the outer surface of the substantiallyrigid annular member 12. The movable central piece can also be made tohave any combination of curved and flat surfaces defined at its innerand outer surfaces, the inner surface being the surface at the corneaand the outer surface being the surface directed generally away from thecornea.

With reference to FIG. 15, the movable central piece 16 may also includea centrally disposed projection 16P directed toward the cornea. Theprojection 16P is preferably created by extending the transparent solidmaterial in toward the cornea at the center of the movable central piece16.

Alternative Embodiment for Measuring Intraocular Pressure by Applanation

With reference to FIG. 16, an alternative embodiment of the system formeasuring intraocular pressure by applanation will now be described. Thealternative embodiment preferably utilizes the version of the contactdevice 2 which includes a transparent central portion.

According to the alternative embodiment, the schematically illustratedcoil 30 of the actuation apparatus includes an iron core 30A forenhancing the magnetic field produced by the coil 30. The iron core 30Apreferably has an axially extending bore hole 30B (approximately 6millimeters in diameter) which permits the passage of light through theiron core 30A and also permits mounting of two lenses L3 and L4 therein.

In order for the system to operate successfully, the strength of themagnetic force applied by the coil 30 on the movable central piece, 16should be sufficient to applanate patients' corneas over at least thefull range of intraocular pressures encountered clinically (i.e. 5-50 mmHg). According to the illustrated alternative embodiment, intraocularpressures ranging from 1 to over 100 mm of mercury can be evaluatedusing the present invention. The forces necessary to applanate againstsuch intraocular pressures may be obtained with reasonablystraightforward designs and inexpensive materials as will bedemonstrated by the following calculations:

It is known that the force F exerted by an external magnetic field on asmall magnet equals the magnet's magnetic dipole moment m multiplied bythe gradient of the external field's magnetic induction vector “grad B”acting in the direction of the magnet's dipole moment.F=m*grad B  (1)

The magnetic dipole moment m for the magnetic version of the movablecentral piece 16 can be determined using the following formula:m=(B*V)/u ₀  (2)where B is the magnetic induction vector just at the surface of one ofthe poles of the movable central piece 16, V is its volume, and u₀ isthe magnetic permeability of free space which has a value of 12.57*10⁻⁷Henry/meter.

A typical value of B for magnetized Alnico movable central pieces 16 is0.5 Tesla. If the movable central piece 16 has a thickness of 1 mm, adiameter of 5 mm, and 50% of its initial volume is machined away, itsvolume V=9.8 cubic millimeters (9.8*10⁻⁹ cubic meters. Substitutingthese values into Equation 2 yields the value for the movable centralpiece's magnetic dipole moment, namely, m=0.00390 Amp*(Meter)².

Using the foregoing calculations, the specifications of the actuationapparatus can be determined. The magnetic field gradient “grad B” is afunction of the distance x measured from the front face of the actuationapparatus and may be calculated as follows:

$\;\begin{matrix}{{{grad}\mspace{14mu} B} = \frac{u_{0}*X*N*I*({RAD})^{2}*\{ {\lbrack {( {x + L} )^{2} + {RAD}^{2}} \rbrack^{{- 3}/2} - \lbrack {x^{2} + {RAD}^{2}} \rbrack^{{- 3}/2}} \}}{2*L}} & (3)\end{matrix}$where X is the magnetic susceptibility of the iron core, N is the numberof turns in the coil's wire, I is the electric current carried by thewire, L is the length of the coil 30, and RAD is the radius of the coil30.

The preferred values for these parameters in the alternative embodimentare: X=500, N=200, I=1.0 Amp, L=0.05 meters, and RAD=0.025 meters. It isunderstood, however, that the present invention is not limited to thesepreferred parameters. As usual, u₀=12.57*10⁻⁷ Henry/meter.

The force F exerted by the magnetic actuation apparatus on the movablecentral piece 16 is found from Equation 1 using the aforementionedpreferred values as parameters in Equation 3, and the above result form=0.00390 Amp*(Meter)2. A plot of F as a function of the distance xseparating the movable central piece 16 from the pole of the magneticactuation apparatus appears as FIG. 16A.

Since a patient's cornea 4, when covered by the contact device 2 whichholds the movable central piece 16, can be placed conveniently at adistance x=2.5 cm (0.025 m) from the actuation apparatus, it is notedfrom FIG. 16A that the magnetic actuation force is approximately F=0.063Newtons.

This force is then compared to F_(required) which is the force actuallyneeded to applanate a cornea 4 over a typical applanation area when theintraocular pressure is as high as 50 mm Hg. In Goldman tonometry, thediameter of the applanated area is approximately 3.1 mm and thereforethe typical applanated AREA will equal 7.55 mm². The typical maximumpressure of50 mm Hg can be converted to metric form, yielding a pressureof 0.00666 Newtons/mm². The value of F_(required) then can be determinedusing the following equation:F_(required)=PRESSURE*AREA  (4)

After mathematical substitution, F_(required)=0.050 Newtons. Comparingthe calculated magnetic actuation force F to the force requiredF_(required), it becomes clear that F_(required) is less than theavailable magnetic driving force F. Therefore, the maximum force neededto applanate the cornea 4 for intraocular pressure determinations iseasily achieved using the actuation apparatus and movable central piece16 of the present invention.

It is understood that, if a greater force becomes necessary for whateverreason (e.g, to provide more distance between the contact device 2 andthe actuation apparatus), the various parameters can be manipulatedand/or the current in the coil 30 can be increased to achieve asatisfactory arrangement.

In order for the actuation apparatus to properly actuate the movablecentral piece 16 in a practical way, the magnetic actuation force (andthe associated magnetic field) should increase from zero, reach amaximum in about 0.01 sec., and then return back to zero inapproximately another 0.01 sec. The power supply to the actuationapparatus therefore preferably includes circuitry and a power sourcecapable of driving a “current pulse” of peak magnitude in the 1 ampererange through a fairly large inductor (i.e. the coil 30).

For Asingle-pulse@ operation, a DC-voltage power supply can be used tocharge a capacitor C through a charging resistor. One side of thecapacitor is grounded while the other side (“high” side) maybe at a 50volt DC potential. The “high” side of the capacitor can be connected viaa high current-carrying switch to a “discharge circuit” consisting ofthe coil 30 and a damping resistor R. This arrangement yields an R-L-Cseries circuit similar to that which is conventionally used to generatelarge pulses of electrical current for such applications as obtaininglarge pulsed magnetic fields and operating pulsed laser power systems.By appropriately choosing the values of the electrical components andthe initial voltage of the capacitor, a Acurrent pulse@ of the kinddescribed above can be generated and supplied to the coil 30 to therebyoperate the actuation apparatus.

It is understood, however, that the mere application of a current pulseof the kind described above to a large inductor, such as the coil 30,will not necessarily yield a zero magnetic field after the current pulsehas ended. Instead, there is usually an undesirable residual magneticfield from the iron-core 30A even though no current is flowing in thecoil 30. This residual field is caused by magnetic hysteresis and wouldtend to produce a magnetic force on the movable central piece 16 whensuch a force is not wanted.

Therefore, the alternative embodiment preferably includes means forzeroing the magnetic field outside the actuation apparatus afteroperation thereof. Such zeroing can be provided by a demagnetizingcircuit connected to the iron-core 30A.

Methods for demagnetizing an iron-core are generally known and are easyto implement. It can be done, for example, by reversing the current inthe coil repeatedly while decreasing its magnitude. The easiest way todo this is by using a step-down transformer where the input is asinusoidal voltage at 60 Hz which starts at a “line voltage” of 110 VACand is gradually dampened to zero volts, and where the output of thetransformer is connected to the coil 30.

The actuation apparatus therefore may include two power circuits,namely, a “single pulse” current source used for conducting applanationmeasurements and a “demagnetization circuit” for zeroing the magneticfield of the coil 30 immediately after each applanation measurement.

As illustrated in FIG. 16 and more specifically in FIG. 17, thealternative embodiment used for applanation also includes an alternativeoptical alignment system. Alignment is very important because, asindicated by the graph of FIG. 16A, the force exerted by the actuationapparatus on the movable central piece 16 depends very much on theirrelative positions. In addition to the movable central piece's axiallocation with respect to the actuation apparatus (x-direction), themagnetic force exerted on the movable central piece 16 also depends onits lateral (y-direction) and vertical (z-direction) positions, as wellas on its orientation (tip and tilt) with respect to the central axis ofthe actuation apparatus.

Considering the variation of force F with axial distance x shown in FIG.16A, it is clear that the movable central piece 16 should be positionedin the x-direction with an accuracy of about ±1 mm for reliablemeasurements. Similarly, since the diameter of the coil 30 is preferably50 mm, the location of the movable central piece 16 with respect to they and z directions (i.e. perpendicular to the longitudinal axis of thecoil 30) should be maintained to within ±2 mm (a region where themagnetic field is fairly constant) of the coil's longitudinal axis.

Finally, since the force on the movable central piece 16 depends on thecosine of the angle between the coil's longitudinal axis and the tip ortilt angle of the movable central piece 16, it is important that therange of the patient's gaze with respect to the coil's longitudinal axisbe maintained within about ±2 degrees for reliable measurements.

In order to satisfy the foregoing criteria, the alternative opticalalignment system facilitates precise alignment of the patient's cornealvertex (situated centrally behind the movable central piece 16) with thecoil's longitudinal axis, which precise alignment can be achievedindependently by a patient without the assistance of a trained medicaltechnician or health care professional.

The alternative optical alignment system functions according to howlight reflects and refracts at the corneal surface. For the sake ofsimplicity, the following description of the alternative opticalalignment system and FIGS. 16 and 17 does not refer specifically to theeffects of the movable central piece's transparent central portion onthe operation of the optical system, primarily because the transparentcentral portion of the movable central piece 16 is preferably arrangedso as not to affect the behavior of optical rays passing through themovable central piece 16.

Also, for the sake of simplicity, FIG. 17 does not show the iron core30A and its associated bore 30B, though it is understood that thealignment beam (described hereinafter) passes through the bored hole 30Band that the lenses L3 and L4 are mounted within the bored hole 30B.

As illustrated in FIG. 16, a point-like source 350 of light such as anLED is located at the focal plane of a positive (i.e., convergent) lensL1. The positive lens L1 is arranged so as to collimate a beam of lightfrom the source 350. The collimated beam passes through a beam splitterBS1 and a transmitted beam of the collimated beam continues through thebeam splitter BS1 to a positive lens L2. The positive lens L2 focusesthe transmitted beam to a point within lens L3 located at the focalplane of a lens L4. The light rays passing through L4 are collimatedonce again and enter the patient's eye where they are focused on theretina 5. The transmitted beam is therefore perceived by the patient asa point-like light.

Some of the rays which reach the eye are reflected from the cornealsurface in a divergent manner due to the cornea's preapplanationcurvature, as shown in FIG. 18, and are returned back to the patient'seye by a partially mirrored planar surface of the lens L4. These raysare perceived by the patient as an image of the corneal reflection whichguides the patient during alignment of his/her eye in the instrument aswill be described hereinafter.

Those rays which are reflected by the convex cornea 4 and pass fromright-to-left through the lens L4 are made somewhat more convergent bythe lens L4. From the perspective of lens L3, these rays appear to comefrom a virtual point object located at the focal point. Therefore, afterpassing through L3, the rays are once again collimated and enter thelens L2 which focuses the rays to a point on the surface of the beamsplitter BS1. The beam splitter BS1 is tilted at 45 degrees andconsequently deflects the rays toward a lens L5 which, in turn,collimates the rays. These rays then strike the surface of a tiltedreflecting beam splitter BS2. The collimated rays reflected from thebeam splitter BS2 enter lens L6 which focuses them onto the smallaperture of a silicon photodiode which functions as an alignment sensorD1.

Therefore, when the curved cornea 4 is properly aligned, an electriccurrent is produced by the alignment sensor D1. The alignment system isvery sensitive because it is a confocal arrangement (i.e., the pointimage of the alignment light due to the corneal reflection—Purkinjeimage—in its fiducial position is conjugate to the small light-sensitiveaperture of the silicon photodiode). In this manner, an electricalcurrent is obtained from the alignment sensor only when the cornea 4 isproperly aligned with respect to the lens L4 which, in turn, ispreferably mounted at the end of the magnetic actuation apparatus. Thefocal lengths of all the lenses shown in FIG. 17 are preferably 50 mmexcept for the lens L3 which preferably has a focal length of 100 MM.

An electrical circuit capable of operating the alignment sensor D1 isstraight-forward to design and build. The silicon photodiode operateswithout any bias voltage (“photovoltaic mode@) thus minimizing inherentdetector noise. In this mode, a voltage signal, which corresponds to thelight level on the silicon surface, appears across a small resistorspanning the diode's terminals. Ordinarily this voltage signal is toosmall for display or subsequent processing; however, it can be amplifiedmany orders of magnitude using a simple transimpedance amplifiercircuit. Preferably, the alignment sensor D1 is utilized in conjunctionwith such an amplified photodiode circuit.

Preferably, the circuitry connected to the alignment sensor D1 isarranged so as to automatically activate the actuation apparatusimmediately upon detecting via the sensor D1 the existence of properalignment. If, however, the output from the alignment sensor D1indicates that the eye is not properly aligned, the circuitry preferablyprevents activation of the actuation apparatus. In this way, thealignment sensor D1, not the patient, determines when the actuationapparatus will be operated.

As indicated above, the optical alignment system preferably includes anarrangement for guiding the patient during alignment of his/her eye inthe instrument. Such arrangements are illustrated, by way of example, inFIGS. 18 and 19.

The arrangement illustrated in FIG. 18 allows a patient to preciselyposition his/her eye translationally in all x-y-z directions. Inparticular, the lens L4 is made to include a plano surface, the planosurface being made partially reflective so that a patient is able to seea magnified image of his/her pupil with a bright point source of lightlocated somewhere near the center of the iris. This point source imageis due to the reflection of the incoming alignment beam from the curvedcorneal surface (called the first Purkinje image) and its subsequentreflection from the mirrored or partially reflecting piano surface ofthe lens L4. Preferably, the lens L4 makes the reflected rays parallelas they return to the eye which focuses them onto the retina 5.

Although FIG. 18 shows the eye well aligned so that the rays are focusedat a central location on the surface of the retina 5, it is understoodthat movements of the eye toward or away (x-direction) from the lens L4will blur the image of the corneal reflection, and that movements of theeye in either the y or z direction will tend to displace the cornealreflection image either to the right/left or up/down.

The patient therefore performs an alignment operation by gazing directlyat the alignment light and moving his/her eye slowly in three dimensionsuntil the point image of the corneal reflection is as sharp as possible(x-positioning) and merges with the point image of the alignment light(y & z positioning) which passes straight through the cornea 4.

As illustrated in FIG. 19, the lens L4 need not have a partiallyreflective portion if the act of merely establishing a proper directionof gaze provides sufficient alignment.

Once alignment is achieved, a logic signal from the optical alignmentsystem activates the “pulse circuit” which, in turn, powers theactuation apparatus. After the actuation apparatus is activated, themagnetic field at the patient's cornea increases steadily for a timeperiod of about 0.01 sec. The effect of this increasing field is toapply a steadily increasing force to the movable central piece 16resting on the cornea which, in turn, causes the cornea 4 to flattenincreasingly over time. Since the size of the applanation area isproportional to the force on the movable central piece 16 (andPressure=Force/Area), the intraocular pressure (IOP) is found bydetermining the ratio of the force to the area applanated by the force.

In order to detect the applanated area and provide an electrical signalindicative of the size of the applanated area, the alternativeembodiment includes an applanation sensor D2. The rays that arereflected from the applanated corneal surface are reflected in agenerally parallel manner by virtue of the flat surface presented by theapplanated cornea 4. As the rays pass from right-to-left through thelens L4, they are focused within the lens L3 which, in turn, is in thefocal plane of the lens L2. Consequently, after passing through the lensL2, the rays are once again collimated and impinge on the surface ofbeam splitter BS1. Since the beam splitter BS1 is tilted at 45 degrees,the beam splitter BS1 deflects these collimated rays toward the lens L5which focuses the rays to a point at the center of beam splitter BS2.The beam splitter BS2 has a small transparent portion or hole in itscenter which allows the direct passage of the rays on to the lens L7(focal length of preferably 50 mm). The lens L7 pertains to anapplanation sensing arm of the alternative embodiment.

The focal spot on the beam splitter BS2 is in the focal plane of thelens L7. Consequently, the rays emerging from the lens L7 are once againcollimated. These collimated rays impinge on the mirror M1, preferablyat a 45 degree angle, and are deflected toward a positive lens L8 (focallength of 50 mm) which focuses the rays onto the small aperture of asilicon photodiode which defines the applanation sensor D2.

It is understood that rays which impinge upon the cornea 4 slightly offcenter tend to be reflected away from the lens L4 when the cornea'scurvature remains undisturbed. However, as applanation progresses andthe cornea becomes increasingly flat, more of these rays are reflectedback into the lens L4. The intensity of light on the applanation sensorD2 therefore increases, and as a result, an electric current isgenerated by the applanation sensor D2, which electric current isproportional to the degree of applanation.

Preferably, the electrical circuit utilized by the applanation sensor D2is identical or similar to that used by the alignment sensor D1.

The electric signal indicative of the area of applanation can then becombined with signals indicative of the time it takes to achieve suchapplanation and/or the amount of current (which, in turn, corresponds tothe applied force) used to achieve the applanation, and this combinationof information can be used to determine the intraocular pressure usingthe equation Pressure=Force/Area.

The following are preferred operational steps for the actuationapparatus during a measurement cycle:

1) While the actuation apparatus is OFF, there is no magnetic fieldbeing directed toward the contact device 2.

2) When the actuation apparatus is turned ON, the magnetic fieldinitially remains at zero.

3) Once the patient is in position, the patient starts to align his/hereye with the actuation apparatus. Until the eye is properly aligned, themagnetic field remains zero.

4) When the eye is properly aligned (as automatically sensed by theoptical alignment Sensor), the magnetic field (driven by a steadilyincreasing electric current) starts to increase from zero.

5) During the time period of the current increase (approximately 0.01sec.), the force on the movable central piece also increases steadily.

6) In response to the increasing force on the movable central piece, thesurface area of the cornea adjacent to the movable central piece isincreasingly flattened.

7) Light from the flattened surface area of the cornea is reflectedtoward the detecting arrangement which detects when a predeterminedamount of applanation has been achieved. Since the amount of lightreflected straight back from the cornea is proportional to the size ofthe flattened surface area, it is possible to determine exactly when thepredetermined amount of applanation has been achieved, preferably acircular area of diameter 3.1 mm, of the cornea. It is understood,however, that any diameter ranging from 0.10 mm to 10 mm can beutilized.

8) The time required to achieve applanation of the particular surfacearea (i.e, the predetermined amount of applanation) is detected by atiming circuit which is part of the applanation detecting arrangement.Based on prior calibration and a resulting conversion table, this timeis converted to an indication of intraocular pressure. The longer thetime required to applanate a specific area, the higher the intraocularpressure, and vice versa.

9) After the predetermined amount of applanation is achieved, themagnetic field is turned OFF.

10) The intraocular pressure is then displayed by a readout meter, andall circuits are preferably turned completely OFF for a period of 15seconds so that the automatic measurement cycle will not be immediatelyrepeated if the patient's eye remains aligned. It is understood,however, that the circuits may remain ON and that a continuousmeasurement of intraocular pressure may be achieved by creating anautomatic measurement cycle. The data provided by this automaticmeasurement cycle then may be used to calculate blood flow.

11) If the main power supply has not been turned OFF, all circuits areturned back ON after 15 seconds and thus become ready for the nextmeasurement.

Although there are several methods for calibrating the various elementsof the system for measuring intraocular pressure by applanation, thefollowing are illustrative examples of how such calibration can beachieved:

Initially, after manufacturing the various components, each component istested to ensure the component operates properly. This preferablyincludes verifying that there is free piston-like movement (no twisting)of the movable central piece in the contact device; verifying thestructural integrity of the contact device during routine handling;evaluating the magnetic field at the surface of the movable centralpiece in order to determine its magnetic dipole moment (when magneticactuation is utilized); verifying that the electrical current pulsewhich creates the magnetic field that actuates the magneticallyresponsive element of the movable central piece, has an appropriate peakmagnitude and duration, and ensuring that there is no “ringing”;verifying the efficacy of the “demagnetization circuit” at removing anyresidual magnetization in the iron-core of the actuation apparatus afterit has been pulsed; measuring the magnetic field as a function of timealong and near the longitudinal axis of the coil where the movablecentral piece will eventually be placed; determining and plotting grad Bas a function of time at several x-locations (i.e., at several distancesfrom the coil) ; and positioning the magnetic central piece (contactdevice) at several x-locations along the coil's longitudinal axis anddetermining'the force F acting on it as a function of time duringpulsed-operation of the actuation apparatus.

Next, the optical alignment system is tested for proper operation. Whenthe optical alignment system comprises the arrangement illustrated inFIGS. 16 and 17, for example, the following testing and calibrationprocedure may be used:

a) First, a convex glass surface (one face of a lens) having a radius ofcurvature approximately the same as that of the cornea is used tosimulate the cornea and its surface reflection. Preferably, this glasssurface is placed in a micrometer-adjusted mounting arrangement alongthe longitudinal axis of the coil. The micrometer-adjusted mountingarrangement permits rotation about two axes (tip & tilt) and translationin three-dimensional x-y-z space.

b) With the detector D1 connected to a voltage or current meter, theconvex glass surface located at its design distance of 25 mm from lensL4 will be perfectly aligned (tip/tilt/x/y/z) by maximizing the outputsignal at the read-out meter.

c) After perfect alignment is achieved, the alignment detectionarrangement is “detuned” for each of the positional degrees of freedom(tip/tilt/x/y/z) and curves are plotted for each degree of freedom tothereby define the system's sensitivity to alignment.

d) The sensitivity to alignment will be compared to the desiredtolerances in the reproducibility of measurements and also can be basedon the variance of the magnetic force on the movable central piece as afunction of position.

e) Thereafter, the sensitivity of the alignment system can be changed asneeded by such procedures as changing the size of the aperture in thesilicon photodiode which functions as the alignment sensor D1, and/orchanging an aperture stop at lens L4.

Next, the detection arrangement is tested for proper operation. When thedetection arrangement comprises the optical detection arrangementillustrated in FIG. 16, for example, the following testing andcalibration procedure may be used:

a) A flat glass surface (e.g., one face of a short polished rod) with adiameter of preferably 4-5 mm is used to simulate the applanated corneaand its surface reflection.

b) A black, opaque aperture defining mechanism (which defines clearinner apertures with diameters ranging from 0.5 to 4 mm and which has anouter diameter the same as that of the rod) is arranged so as topartially cover the face of the rod, thus simulating various stages ofapplanation.

c) The flat surfaced rod is placed in a mount along the longitudinalaxis of the coil in a micrometer-adjusted mounting arrangement that canrotate about two axes (tip & tilt) and translate in three-dimensionalx-y-z space.

d) The applanation sensor D2 is then connected to a voltage or currentmeter, while the rod remains located at its design distance of 25 mmfrom the lens L4 where it is perfectly aligned (tip/tilt/x/y/z) bymaximizing the output signal from the applanation sensor D2. Alignment,in this case, is not sensitive to x-axis positioning.

e) After perfect alignment is achieved, the alignment is “detuned” foreach of the positional degrees of freedom (tip/tilt/x/y/z) and curvesare plotted for each degree of freedom thus defining the system'ssensitivity to alignment. Data of this kind is obtained for thevariously sized apertures (i.e. different degrees of applanation) at theface of the rod.

f) The sensitivity to alignment is then compared to the tolerancesrequired for reproducing applanation measurements which depends, inpart, on the results obtained in the aforementioned testing andcalibration method associated with the alignment apparatus.

g) The sensitivity of the applanation detecting arrangement is thenchanged as needed by such procedures as changing the size of theaperture in front of the applanation sensor D2 and/or changing theaperture stop (small hole) at the beam splitter BS2.

Further calibration and in-vitro measurements can be carried out asfollows: After the aforementioned calibration and testing procedureshave been carried out on the individual subassemblies, all parts can becombined and the system tested as an integrated unit. For this purpose,ten enucleated animal eyes and ten enucleated human eyes are measured intwo separate series. The procedures for both eye types are the same. Theeyes are mounted in non-magnetic holders, each having a central openingwhich exposes the cornea and part of the sclera. A 23 gauge needleattached to a short piece of polyethylene tubing is then inserted behindthe limbus through the sclera and ciliary body and advanced so that thetip passes between the lens and iris. Side ports are drilled in thecannulas about 2 mm from the tip to help avoid blockage of the cannulaby the iris or lens. This cannula is attached to a pressure transducerwith an appropriate display element. A normal saline reservoir ofadjustable height is also connected to the pressure transducer tubingsystem. The hydrostatic pressure applied to the eye by this reservoir isadjustable between 0 and 50 mm Hg, and intraocular pressure over thisrange can be measured directly with the pressure transducer.

In order to verify that the foregoing equipment is properly set up foreach new eye, a standard Goldman applanation tonometer can be used toindependently measure the eye's intraocular pressure at a single heightof the reservoir. The intraocular value measured using the Goldmansystem is then compared to a simultaneously determined intraocularpressure measured by the pressure transducer. Any problems encounteredwith the equipment can be corrected if the two measurements aresignificantly different.

The reservoir is used to change in 5 mm Hg sequential steps theintraocular pressure of each eye over a range of pressures from 5 to 50mm Hg. At each of the pressures, a measurement is taken using the systemof the present invention. Each measurement taken by the presentinvention consists of recording three separate time-varying signals overthe time duration of the pulsed magnetic field. The three signalsare: 1) the current flowing in the coil of the actuation apparatus as afunction of time, labelled I (t), 2) the voltage signal as a function oftime from the applanation detector D2, labelled APPLN (t), and 3) thevoltage signal as a function of time from the alignment sensor D1,labelled ALIGN (t). The three signals, associated with each measurement,are then acquired and stored in a computer equipped with a multi-input“data acquisition and processing” board and related software.

The computer allows many things to be done with the data including: 1)recording and storing many signals for subsequent retrieval, 2)displaying graphs of the signals versus time, 3) numerical processingand analyses in any way that is desired, 4) plotting final results, 5)applying statistical analyses to groups of data, and 6) labeling thedata (e.g. tagging a measurement set with its associated intraocularpressure).

The relationship between the three time-varying signals and intraocularpressure are as follows:

1. I(t) is an independent input signal which is consistently applied ascurrent pulse from the power supply which activates the actuationapparatus. This signal I (t) is essentially constant from onemeasurement to another except for minor shot-to-shot variations. I (t)is a “reference” waveform against which the other waveforms, APPLN (t)and ALIGN (t) are compared as discussed further below.

2. APPLN(t) is a dependent output signal. APPLN(t) has a value of zerowhen I(t) is zero (i.e. at the very beginning of the current pulse inthe coil of the actuation apparatus. The reason for this is that whenI=0, there is no magnetic field and, consequently, no applanation forceon the movable central piece. As I (t) increases, so does the extent ofapplanation and, correspondingly, so does APPLN(t). It is important tonote that the rate at which APPLN(t) increases with increasing I(t)depends on the eye's intraocular pressure. Since eyes with lowintraocular pressures applanate more easily than eyes with highintraocular pressures in response to an applanation force, it isunderstood that APPLN(t) increases more rapidly for an eye having a lowintraocular pressure than it does for an eye having a high intraocularpressure. Thus, APPLN (t) increases from zero at a rate that isinversely proportional to the intraocular pressure until it reaches amaximum value when full applanation is achieved.

3. ALIGN(t) is also a dependent output signal. Assuming an eye isaligned in the setup, the signal ALIGN(t) starts at some maximum valuewhen I(t) is zero (i.e. at the very beginning of the current pulse tothe coil of the actuation apparatus). The reason for this is that whenI=0, there is no magnetic field and, consequently, no force on themovable central piece which would otherwise tend to alter the cornea'scurvature. Since corneal reflection is what gives rise to the alignmentsignal, as I(t) increases causing applanation (and, correspondingly, adecrease in the extent of corneal curvature), the signal ALIGN (t)decreases until it reaches zero at full applanation. It is important tonote that the rate at which ALIGN (t) decreases with increasing I(t)depends on the eye's intraocular pressure. Since extraocular pressureapplanate more easily than eyes with high intraocular pressure, it isunderstood that ALIGN (t) decreases more rapidly for an eye having a lowintraocular pressure than for an eye having a high intraocular pressure.Thus, ALIGN(t) decreases from some maximum value at a rate that isinversely proportional to the intraocular pressure until it reaches zerowhen full applanation is achieved.

From the foregoing, it is clear that the rate of change of both outputsignals, APPLN and ALIGN, in relation to the input signal I is inverselyproportional to the intraocular pressure. Therefore, the measurement ofintraocular pressure using the present invention may depend ondetermining the SLOPE of the AAPPLN versus I@ measurement data (also,although probably with less certainty, the slope of the “ALIGN versus I”measurement data).

For the sake of brevity, the following description is limited to the“APPLN versus I” data; however, it is understood that the “ALIGN versusI” data can be processed in a similar manner.

Plots of AAPPLN versus I@ can be displayed on the computer monitor forthe various measurements (all the different intraocular pressures foreach and every eye) and regression analysis (and other data reductionalgorithms) can be employed in order to obtain the “best fit” SLOPE foreach measurement. Time can be spent in order to optimize this datareduction procedure. The end result of a series of pressure measurementsat different intraocular pressures on an eye (determined by theaforementioned pressure transducer) will be a corresponding series ofSLOPE's (determined by the system of the present invention).

Next, a single plot is prepared for each eye showing SLOPE versusintraocular pressure data points as well as a best fitting curve throughthe data. Ideally, all curves for the 10 pig eyes are perfectlycoincident—with the same being true for the curves obtained for the 10human eyes. If the ideal is realized, any of the curves can be utilized(since they all are the same) as a CALIBRATION for the presentinvention. In practice, however, the ideal is probably not realized.

Therefore, all of the SLOPE versus intraocular pressure data for the 10pig eyes is superimposed on a single plot (likewise for the SLOPE versusintraocular pressure data for the 10 human eyes). Such superimposinggenerally yields an “averaged” CALIBRATION curve, and also indication ofthe reliability associated with the CALIBRATION.

Next, the data in the single plots can be analyzed statistically (onefor pig eyes and one for human eyes) which, in turn, shows a compositeof all the SLOPE versus intraocular pressure data. From the statisticalanalysis, it is possible to obtain: 1) an averaged CALIBRATION curve forthe present invention from which one can obtain the Amost likelyintraocular pressure” associated with a measured SLOPE value, 2) theStandard Deviation (or Variance) associated with any intraocularpressure determination made using the present invention, essentially thepresent invention's expected “ability” to replicate measurements, and 3)the “reliability” or “accuracy” of the present invention's CALIBRATIONcurve which is found from a “standard-error-of-the mean” analysis of thedata.

In addition to data obtained with the eyes aligned, it is also possibleto investigate the sensitivity of intraocular pressure measurements madeusing the present invention, to translational and rotationalmisalignment.

Alternative Embodiment of Measuring Intraocular Pressure by Indentation

With reference to FIGS. 20A and 20B, an alternative embodiment formeasuring intraocular pressure by indentation will now be described.

The alternative embodiment includes an indentation distance detectionarrangement and contact device. The contact device has a movable centralpiece 16 of which only the outside surface is illustrated in FIGS. 20Aand 20B. The outside surface of the movable central piece 16 is at leastpartially reflective.

The indentation distance detection arrangement includes two converginglenses L1 and L2; a beam splitter BS1; a light source LS for emitting abeam of light having a width w; and a light detector LD responsive tothe diameter of a reflected beam impinging on a surface thereof.

FIG. 20A illustrates the alternative embodiment prior to actuation ofthe movable central piece 16. Prior to actuation, the patient is alignedwith the indentation distance detection arrangement so that the outersurface of the movable central piece 16 is located at the focal point ofthe converging lens L2. When the movable central piece 16 is so located,the beam of light from the light source LS strikes the beam splitter BSand is deflected through the converging lens L1 to impinge as a point onthe reflective outer surface of the movable central piece 16. Thereflective outer surface of the movable central piece 16 then reflectsthis beam of light back through the converging lens L1, through the beamsplitter BS, and then through the converging lens L2 to strike a surfaceof the light detector LD. Preferably, the light detector LD is locatedat the focal point of the converging lens L2 so that the reflected beamimpinges on a surface of the light detector LD as a point of virtuallyzero diameter when the outer surface of the movable central pieceremains at the focal point of the converging lens L1.

Preferably, the indentation distance detection arrangement is connectedto a display device so as to generate an indication of zero displacementwhen the outer surface of the movable central piece 16 has yet to bedisplaced, as shown in FIG. 20A.

By subsequently actuating the movable central piece 16 using anactuating device (preferably, similar to the actuating devices describedabove), the outer surface of the movable central piece 16 movesprogressively away from the focal point of the converging lens L1, asillustrated in FIG. 20B. As a result, the light beam impinging on thereflective outer surface of the movable central piece 16 has aprogressively increasing diameter. This progressive increase in diameteris proportional to the displacement from the focal point of theconverging lens L1. The resulting reflected beam therefore has adiameter proportional to the displacement and passes back through theconverging lens L1, through the beam splitter BS, through the converginglens C2 and then strikes the surface of the light detector LD with adiameter proportional to the displacement of the movable central piece16. Since the light detector LD is responsive, as indicated above, tothe diameter of the reflected light beam, any displacement of themovable central piece 16 causes a proportional change in output from thelight detector LD.

Preferably, the light detector LD is a photoelectric converter connectedto the aforementioned display device and capable of providing an outputvoltage proportional to the diameter of the reflected light beamimpinging upon the light detector LD. The display device thereforeprovides a visual indication of displacement based on the output voltagefrom the light detector LD.

Alternatively, the output from the light detector LD may be connected toan arrangement, as described above, for providing an indication ofintraocular pressure based on the displacement of the movable centralpiece 16.

Additional Capabilities

Generally, the present apparatus and method makes it possible toevaluate intraocular pressure, as indicated above, as well as ocularrigidity, eye hydrodynamics such as outflow facility and inflow rateof-eye fluid, eye hemodynamics such as the pressure in the episcleralveins and the pulsatile ocular blood flow, and has also the ability toartificially increase intraocular pressure, as well as the continuousrecording of intraocular pressure.

With regard to the measurement of intraocular pressure by applanation,the foregoing description sets forth several techniques foraccomplishing such measurement, including a variable force techniquewherein the force applied against the cornea varies with time. It isunderstood, however, that a variable area method can also beimplemented.

The apparatus can evaluate the amount of area applanated by a knownforce. The pressure is calculated by dividing the force by the amount ofarea that is applanated. The amount of area applanated is determinedusing the optical means and/or filters previously described.

A force equivalent to placing 5 gram of weight on the cornea, forexample, will applanate a first area if the pressure is 30 mmHg, asecond area if the pressure is 20 mmHg, a third area if the pressure is15 mmHg and so on. The area applanated is therefore indicative ofintraocular pressure.

Alternatively, intraocular pressure can be measured using a non-rigidinterface and general applanation techniques. In this embodiment, aflexible central piece enclosed by the magnet of the movable centralpiece is used and the transparent part of the movable central piece actslike a micro-balloon. This method is based on the principle that theinterface between two spherical balloons of unequal radius will be flatif the pressures in the two balloons are equal. The central piece withthe balloon is pressed against the eye until the eye/central pieceinterface is planar as determined by the aforementioned optical means.

Also, with regard to the previously described arrangement which measuresintraocular pressure by indentation, an alternative method can beimplemented with such an embodiment wherein the apparatus measures theforce required to indent the cornea by a predetermined amount. Thisamount of indentation is determined by optical means as previouslydescribed. The movable central piece is pressed against the cornea toindent the cornea, for example, 0.5 mm (though it is understood thatvirtually any other depth can be used). Achievement of the predetermineddepth is detected by the previously described optical means and filters.According to tables, the intraocular pressure can be determinedthereafter from the force.

Yet another technique which the present invention facilitates use of isthe ballistic principle. According to the ballistic principle, aparameter of a collision between the known mass of the movable centralpiece and the cornea is measured. This measured parameter is thenrelated theoretically or experimentally to the intraocular pressure. Thefollowing are exemplary parameters:

Impact Acceleration

-   -   The movable central piece is directed at the cornea at a well        defined velocity. It collides with the cornea and, after a        certain time of contact, bounces back. The time-velocity        relationships during and after impact can be studied. The        applanating central piece may have a spring connecting to the        rigid annular member of the contact device. If the corneal        surface is hard, the impact time will be short. Likewise, if the        corneal surface is soft the impact time will be longer. Optical        sensors can detect optically the duration of impact and how long        it takes for the movable central piece to return to its original        position.

Impact Duration

-   -   Intraocular pressure may also be estimated by measuring the        duration of contact of a spring driven movable central piece        with the eye. The amount of time that the cornea remains        flattened can be evaluated by the previously described optical        means.

Rebound Velocity

-   -   The distance traveled per unit of time after bouncing is also        indicative of the rebound energy and this energy is proportional        to intraocular pressure.

Vibration Principle

-   -   The intraocular pressure also can be estimated by measuring the        frequency of a vibrating element in contact with the contact        device and the resulting changes in light reflection are related        to the pressure in the eye.

Time

-   -   The apparatus of the present invention can also be used, as        indicated above, to measure the time that it takes to applanate        the cornea. The harder the cornea, the higher the intraocular        pressure and thus the longer it takes to deform the cornea. On        the other hand, the softer the cornea, the lower the intraocular        pressure and thus the shorter it takes to deform the cornea.        Thus, the amount of time that it takes to deform the cornea is        proportional to the intraocular pressure.

Additional uses and capabilities of the present invention relate toalternative methods of measuring outflow facility (tonography). Thesealternative methods include the use of conventional indentationtechniques, constant depth indentation techniques, constant pressureindentation techniques, constant pressure applanation techniques,constant area applanation techniques, and constant force applanationtechniques.

1. Conventional Indentation

When conventional indentation techniques, are utilized, the movablecentral piece of the present invention is used to indent the cornea andthereby artificially increase the intraocular pressure. This artificialincrease in intraocular pressure forces fluid out of the eye morerapidly than normal. As fluid leaves the eye, the pressure graduallyreturns to its original level. The rate at which the intraocularpressure falls depends on how well the eye's drainage system isfunctioning. The drop in pressure as a function of time is used tocalculated the C value or coefficient of outflow facility. The C valueis indicative of the degree to which a change in intraocular pressurewill cause a change in the rate of fluid outflow. This, in turn, isindicative of the resistance to outflow provided by the eye's drainagesystem. The various procedures for determining outflow facility aregenerally known as tonography and the C value is typically expressed interms of microliters per minute per millimeter of mercury. The C valueis determined by raising the intraocular pressure using the movablecentral piece of the contact device and observing the subsequent decayin intraocular pressure with respect to time. The elevated intraocularpressure increases the rate of aqueous outflow which, in turn, providesa change in volume. This change in volume can be calculated from theFriedenwald tables which correlate volume change to pressure changes.The rate of volume decrease equals the rate of outflow. The change inintraocular pressure during the tonographic procedure can be computed asan arithmetical average of pressure increments for successive 2 minuteintervals. The C value is derived then from the following equation:C=ΔV/t*(Pave−Po), in which t is the duration of the procedure, Pave isthe average pressure elevation during the test and can be measured, Pois the initial pressure and it is also measured, and ΔV is differencebetween the initial and final volumes and can be obtained from knowntables. The Flow (AF@) of fluid is then calculated using the formula:F=C*(Po−Pv), in which Pv is the pressure in the episcleral veins whichcan be measured and generally has a constant value of 10.

2. Constant Depth Indentation

When constant depth indentation techniques are utilized, the methodinvolves the use of a variable force which is necessary to cause acertain predetermined amount of indentation in the eye. The apparatus ofthe present invention is therefore configured so as to measure the forcerequired to indent the cornea by a predetermined amount. This amount ofindentation may be detected using optical means as previously described.The movable central piece is pressed against the cornea to indent theeye, for example, by approximately 0.5 mm. The amount of indentation isdetected by the optical means and filters previously described. With thecentral piece indenting the cornea using a force equivalent to a weightof 10 grams, a 0.5 mm indentation will be achieved under normal pressureconditions (e.g., intraocular pressure of 15 mm Hg) and assuming thereis an average corneal curvature. With that amount of indentation andusing standard dimensions for the central piece, 2.5 mm³ of fluid willbe displaced. The force recorded by the present invention undergoes aslow decline and it levels off at a more or less steady state valueafter 2 to 4 minutes. The decay in pressure is measured based on thedifference between the value of the first indentation of the centralpiece and the final level achieved after a certain amount of time. Thepressure drop is due to the return of pressure to its normal value,after it has been artificially raised by the indentation caused by themovable central piece. A known normal value of decay is used as areference and is compared to the values obtained. Since the foregoingprovides a continuous recording of pressure over time, this method canbe an important tool for physiological research by showing, for example,an increase in pressure during forced expiration. The pulse wave andpulse amplitude can also be evaluated and the pulsatile blood flowcalculated.

3. Constant Pressure Indentation

When constant pressure indentation techniques are utilized, theintraocular pressure is kept constant by increasing the magnetic fieldand thereby increasing the force against the cornea as fluid leaks outof the eye. At any constant pressure, the force and rate of outflow arelinearly related according to the Friedenwald tonometry tables. Theintraocular pressure is calculated using the same method as describedfor conventional indentation tonometry. The volume displacement iscalculated using the tonometry tables. The facility of outflow (C) maybe computed using two different techniques. According to the firsttechnique, C can be calculated from two constant pressure tonograms atdifferent pressures according to the equation,C={[(ΔV₁/t₁)−(ΔV₂/t₂)]/(P₁-P2)}, in which 1 corresponds to a measurementat a first pressure and 2 corresponds to a measurement at a secondpressure (which is higher than the first pressure). The second way tocalculate C is from one constant pressure tonogram and an independentmeasure of intraocular pressure using applanation tonometry (P_(a)), inC=[(ΔV/t)/(P_(a)−P_(a)−ΔP_(e))], where ΔP_(e) is a correction factor forrise in episcleral venous pressure with indentation tonometry and P isthe intraocular pressure obtained using indentation tonometry.

4. Constant Pressure Applanation

When constant pressure applanation techniques are utilized, theintraocular pressure is kept constant by increasing the magnetic fieldand thus the force as fluid leaks out of the eye. If the cornea isconsidered to be a portion of a sphere, a mathematical formula relatesthe volume of a spherical segment to the radius of curvature of thesphere and the radius of the base of the segment. The volume displacedis calculated based on the formula V=A²/(4*π*R), in which V is volume, Ais the area of the segment base, and R is the radius of curvature of thesphere (this is the radius of curvature of the cornea). SinceA=weight/pressure, then V-W²/(4*π*R*P²). The weight is constituted bythe force in the electromagnetic field, R is the curvature of the corneaand can be measured with a keratometer, P is the pressure in the eye andcan be measured using the same method as described for conventionalapplanation tonometry. It is therefore possible to calculate the volumedisplaced and the C value or outflow facility. The volume displaced, forexample, can be calculated at 15 second intervals and is plotted as afunction of time.

5. Constant Area Applanation

When constant area applanation techniques are utilized, the methodconsists primarily of evaluating the pressure decay curve while theflattened area remains constant. The aforementioned optical applanationdetecting arrangements can be used in order to keep constant the areaflattened by the movable central piece. The amount of force necessary tokeep the flattened area constant decreases and this decrease isregistered. The amount of volume displaced according to the differentareas of applanation is known. For instance, a 5 mm applanating centralpiece displaces 4.07 mm³ of volume for the average corneal radius of 7.8mm. Using the formula ΔV/Δt=l/(R*ΔP), it is possible to calculate Rwhich is the reciprocal of C. Since a continuous recording of pressureover time is provided, this method can be an important tool for researchand evaluation of blood flow.

6. Constant Force Applanation

When constant force applanation techniques are utilized, the same forceis constantly applied and the applanated area is measured using any ofthe aforementioned optical applanation detection arrangements. Once thearea flattened by a known force is measured, the pressure can becalculated by dividing the force by the amount-of area that isapplanated. As fluid leaves the eye the amount of area applanatedincreases with time. This method consists primarily of evaluating aresulting area augmentation curve while the constant force is applied.The amount of volume displaced according to the different areas ofapplanation is known. Using the formula ΔV/Δt=l/(R*ΔP), it is possibleto calculate R which is the reciprocal of C.

Still additional uses of the present invention relate to detecting thefrequency response of the eye, using indentation tonometry. Inparticular, if an oscillating force is applied using the movable centralpiece 16, the velocity of the movable central piece 16 is indicative ofthe eye's frequency response. The system oscillates at the resonantfrequency determined primarily by the mass of the movable central piece16. By varying the frequency of the force and by measuring the response,the intraocular pressure can be evaluated. The evaluation can be made bymeasuring the resonant frequency and a significant variation in resonantfrequency can be obtained as a function of the intraocular pressure.

The present invention may also be used with the foregoing conventionalindentation techniques, but where the intraocular pressure used forcalculation is measured using applanation principles. Since applanationvirtually does not disturb the hydrodynamic equilibrium because itdisplaces a very small volume, this method can be considered moreaccurate than intraocular pressure measurements made using traditionalindentation techniques.

Another use of the present invention involves a time related way ofmeasuring the resistance to outflow. In particular, the resistance tooutflow is detected by measuring the amount of time necessary totransfigure the cornea with either applanation or indentation. The timenecessary to displace, for example, 5 microliters of eye fluid would beI second for normal patients and above 2 seconds for glaucoma-strickenindividuals.

Yet another use of the present invention involves measuring the inflowof eye fluid. In particular, this measurement is made by applying theformula F=ΔP/R, in which ΔP is P−P_(v), and P is the steady stateintraocular pressure and P_(v) is the episcleral venous pressure which,for purposes of calculation, is considered constant at 10. R is theresistance to outflow, which is the reciprocal of C that can becalculated. F, in units of volume/min, can then be calculated.

The present invention is also useful at measuring ocular rigidity, orthe distensibility of the eye in response to an increased intraocularpressure. The coefficient of ocular rigidity can be calculated using anomogram which is based on two tonometric readings with differentweights. A series of conversion tables to calculate the coefficient ofocular rigidity was developed by Friedenwald. The technique fordetermining ocular rigidity is based on the concept of differentialtonometry, using two indentation tonometric readings with differentweights or more accurately, using one indentation reading and oneapplanation reading and plotting these readings on the nomogram. Sincethe present invention can be used to measure intraocular pressure usingboth applanation and indentation techniques, a more accurate evaluationof the ocular rigidity can be achieved.

Measurements of intraocular pressure using the apparatus of the presentinvention can also be used to evaluate hemodynamics, in particular, eyehemodynamics and pulsatile ocular blood flow. The pulsatile ocular bloodflow is the component of the total ocular arterial inflow that causes arhythmic fluctuation of the intraocular pressure. The intraocularpressure varies with each pulse due to the pulsatile influx of a bolusof arterial blood into the eye with each heartbeat. This bolus of bloodenters the intraocular arteries with each heartbeat causing a temporaryincrease in the intraocular pressure. The period of inflow causes astretching of the eye walls with a concomitant increase in pressurefollowed by a relaxation to the previous volume and a return to theprevious pressure as the blood drains from the eye. If this process ofexpansion during systole (contraction of the heart) and contractionduring diastole (relaxation of the heart) occurs at a certain pulserate, then the blood flow rate would be the incremental change in eyevolume times the pulse rate.

The fact that intraocular pressure varies with time according to thecardiac cycle is the basis for measuring pulsatile ocularblood flow. Thecardiac cycle is approximately in the order of 0.8 Hz. The presentinvention can measure the time variations of intraocular pressure with afrequency that is above the fundamental human heart beat frequencyallowing the evaluation and recording of intraocular pulse. In thenormal human eye, the intraocular pulse has a magnitude of approximately3 mm Hg and is practically synchronous with the cardiac cycle.

As described, measurements of intraocular pressure show a time variationthat is associated with the pulsatile component of arterial pressure.Experimental results provide means of transforming ocular pressurechanges into eye volume changes. Each bolus of blood entering the eyeincreases the ocular volume and the intraocular pressure. The observedchanges in pressure reflect the fact that the eye volume must change toaccommodate changes in the intraocular blood volume induced by thearterial blood pulse. This pulse volume is small relative to the ocularvolume, but because the walls of the eye are stiff, the pressureincrease required to accommodate the pulse volume is significant and canbe measured. Therefore, provided that the relationship between theincreased intraocular pressure and increased ocular volume is known, thevolume of the bolus of fluid can be determined. Since this relationshipbetween pressure change and volume change has been well established(Friedenwald 1937, McBain 1957, Ytteborg 1960, Eisenlohr 1962, McEwen1965), the pressure measurements can be used to obtain the volume of abolus of blood and thereby determine the blood flow.

The output of the tonometer for the instantaneous pressure can beconverted into instantaneous change in eye volume as a function of time.The time derivative of the change in ocular volume is the netinstantaneous pulsatile component of the ocular blood flow. Under theseconditions, the rate of pulsatile blood flow through the eye can beevaluated from the instantaneous measurement of intraocular pressure. Inorder to rapidly quantify and analyze the intraocular pulse, the signalfrom the tonometer may be digitalized and fed into a computer.

Moreover, measurements of intraocular pressure can be used to obtain theintraocular volume through the use of an independently determinedpressure-volume relationship such as with the Friedenwald equation(Friedenwald, 1937). A mathematical model based on experimental datafrom the pressure volume relationship (Friedenwald 1937, McBain 1957,Eisenlohr 1962, McEwen 1965) can also be used to convert a change inocular pressure into a change in ocular volume.

In addition, a model can also be constructed to estimate the ocularblood flow from the appearance of the intraocular pressure waveform. Theflow curve is related to parameters that come from the volume changecurve. This curve is indirectly measured since the intraocular pressureis the actual measured quantity which is transformed into volume changethrough the use of the measured pressure-volume relation. The flow isthen computed by taking the change in volume Vmax−Vmin multiplied by aconstant that is related to the length of the time interval of theinflow and the total pulse length. Known mathematical calculations canbe used to evaluate the pulsatile component of the ocular blood flow.Since the present invention can also be used to measure the ocularrigidity, this parameter of coefficient of ocular rigidity can be usedin order to more precisely calculate individual differences in pulsatileblood flow.

Moreover, since the actuation apparatus 6 and contact device 2 of thepresent invention preferably include transparent portions, the pulsatileblood flow can be directly evaluated optically to quantify the change insize of the vessels with each heart beat. A more precise evaluation ofblood flow therefore can be achieved by combining the changes inintraocular pulse with changes in vessel diameter which can beautomatically measured optically.

A vast amount of data about the vascular system of the eye and centralnervous system can be obtained after knowing the changes in intraocularpressure over time and the amount of pulsatile ocular blood flow. Theintraocular pressure and intraocular pulse are normally symmetrical inpairs of eyes. Consequently, a loss of symmetry may serve as an earlysign of ocular or cerebrovascular disease. Patients afflicted withdiabetes, macular degeneration, and other vascular disorders may alsohave a decreased ocular blood flow and benefit from evaluation of eyehemodynamics using the apparatus of the present invention.

The present invention may also be used to artificially elevateintraocular pressure. The artificial elevation of intraocular pressureis an important tool in the diagnosis and prognosis of eye and braindisorders as well as an important tool for research.

Artificial elevation of intraocular pressure using the present inventioncan be accomplished in different ways. According to one way, the contactdevice of the present invention is modified in shape for placement onthe sclera (white of the eye). This arrangement, which will be describedhereinafter, is illustrated in FIGS. 21-22, wherein the movable centralpiece 16 may be larger in size and is preferably actuated against thesclera in order to elevate the intraocular pressure. The amount ofindentation can be detected by the optical detection system previouslydescribed.

Another way of artificially increasing the intraocular pressure is byplacing the contact device of the present invention on the cornea in thesame way as previously described, but using the movable central piece toapply a greater amount of force to achieve deeper indentation. Thistechnique advantageously allows visualization of the eye while exertingthe force, since the movable central portion of the contact device ispreferably transparent. According to this technique, the size of themovable central piece can also be increased to indent a larger area andthus create a higher artificial increase of intraocular pressure.Preferably, the actuation apparatus also has a transparent centralportion, as indicated above, to facilitate direct visualization of theeye and retina while the intraocular pressure is being increased. Whenthe intraocular pressure exceeds the ophthalmic arterial diastolicpressure, the pulse amplitude and blood flow decreases rapidly. Bloodflow becomes zero when the intraocular pressure is equal or higher thanthe ophthalmic systolic pressure. Thus, by allowing direct visualizationof the retinal vessels, one is able to determine the exact moment thatthe pulse disappears and measure the pressure necessary to promote thecessation of the pulse which, in turn, is the equivalent of the pulsepressure in the ophthalmic artery. The present invention thus allows themeasurement of the pressure in the arteries of the eye.

Also, by placing a fixation light in a back portion of the actuationapparatus and asking the patient to indicate when he/she can no longersee the light, one can also record the pressure at which a patient'svision ceases. This also would correspond to the cessation of the pulsein the artery of the eye. The pressure in which vessels open can also bedetermined by increasing intraocular pressure until the pulse disappearsand then gradually decreasing the intraocular pressure until the pulsereappears. Thus, the intraocular pressure necessary for vessels to opencan be evaluated.

It is important to note that the foregoing measurements can be performedautomatically using an optical detection system, for example, by aiminga light beam at the pulsating blood vessel. The cessation of pulsationcan be optically recognized and the pressure recorded. An attenuation ofpulsations can also be used as the end point and can be opticallydetected. The apparatus also allows direct visualization of the papillaof the optic nerve while an increased intraocular pressure is produced.Thus, physical and chemical changes occurring inside the eye due to theartificial increase in intraocular pressure may be evaluated at the sametime that pressure is measured.

Advantageously, the foregoing, test can be performed on patients withmedia opacities that prevent visualization of the back of the eye. Inparticular, the aforementioned procedure wherein the patient indicateswhen vision ceases is particular useful in patients with mediaopacities. The fading of the peripheral vision corresponds to thediastolic pressure and fading of the central vision corresponds to thesystolic pressure.

The present invention, by elevating the intraocular pressure, asindicated above and by allowing direct visualization of blood vessels inthe back of the eye, may be used for tamponade (blockade of bleeding byindirect application of pressure) of hemorrhagic processes such as thosewhich occur, for example, in diabetes and macular degeneration. Theelevation of intraocular pressure may also be beneficial in thetreatment of retinal detachments.

As yet another use of the present invention, the aforementionedapparatus also can be used to measure outflow pressure of the eye fluid.In order to measure outflow pressure in the eye fluid, the contactdevice is placed on the cornea and a measurable pressure is applied tothe cornea. The pressure causes the aqueous vein to increase in diameterwhen the pressure in the cornea equals the outflow pressure. Thepressure on the cornea is proportional to the outflow pressure. The flowof eye fluid out of the eye is regulated according to Poiseuille's Lawfor laminar currents. If resistance is inserted into the formula, theresult is a formula similar to Ohm's Law. Using these known formulas,the rate of flow (volume per time) can be determined. The change in thediameter of the vessel which is the reference point can be detectedmanually by direct observation and visualization of the change indiameter or can be done automatically using an optical detection systemcapable of detecting a change in reflectivity due to the amount of fluidin the vein and the change in the surface area. The actual cross-sectionof the vein can be detected using an optical detection system.

The eye and the brain are hemodynamically linked by the carotid arteryand the autonomic nervous system. Pathological changes in the carotid,brain, heart, and the sympathetic nervous system can secondarily affectthe blood flow to the eye. The eye and the brain are low vascularresistance systems with high reactivity. The arterial flow to the brainis provided by the carotid artery. The ophthalmic artery branches off ofthe carotid at a 90 degree angle and measures approximately 0.5 mm indiameter in comparison to the carotid which measures 5 mm in diameter.Thus, most processes that affect the flow to the brain will have aprofound effect on the eye. Moreover, the pulsation of the centralretinal artery may be used to determine the systolic pressure in theophthalmic artery, and due to its anatomic relationship with thecerebral circulatory system, the pressure in the brain's vessels can beestimated. Total or partial occlusion of the vascular system to thebrain can be determined by evaluating the ocular blood flow. There arenumerous vascular and nervous system lesions that alter the ocular pulseamplitude and/or the intraocular pressure curve of the eye. Thesepathological situations may produce asymmetry of measurements betweenthe two eyes and/or a decrease of the central retinal artery pressure,decrease of pulsatile blood flow and alter the pulse amplitude.

An obstruction in the flow in the carotid (cerebral circulation) can beevaluated by analyzing the ocular pulse amplitude and area, pulse delayand pulse width, form of the wave and by harmonic analysis of the ocularpulse.

The eye pulsation can be recorded optically according to the change inreflection of the light beam projected to the cornea. The same systemused to record distance traveled by the movable central piece duringindentation can be used on the bare cornea to detect the changes involume that occurs with each pulsation. The optical detection systemrecords the variations in distance from the surface of the cornea thatoccurs with each heart beat. These changes in the position of the corneaare induced by the volume changes in the eye. From the pulsatilecharacter of these changes, the blood flow to the eye can be calculated.

With the aforementioned technique of artificial elevation of pressure,it is possible to measure the time necessary for the eye to recover toits baseline and this recovery time is an indicator of the presence ofglaucoma and of the coefficient of outflow facility.

The present invention may also be used to measure pressure in thevessels on the surface of the eye, in particular the pressure in theepiscleral veins. The external pressure necessary to collapse a vein isutilized in this measurement. The method involves applying a variableforce over a constant area of conjunctive overlying the episcleral veinuntil a desired end point is obtained. The pressure is applied directlyonto the vessel itself and the preferred end point is when the vesselcollapses. However, different end points may be used, such as blanchingof the vessel which occurs prior to the collapse. The pressure of theend point is determined by dividing the force applied by the area of theapplanating central piece in a similar way as is used for tonometry. Thevessel may be observed through a transparent applanating movable centralpiece using a slit-lamp biomicroscope. The embodiment for this techniquepreferably includes a modified contact device which fits on the sclera(FIG. 23). The preferred size of the tip ranges from 250 micrometers to500 micrometers. Detection of the end point can be achieved eithermanually or automatically.

According to the manual arrangement, the actuation apparatus isconfigured for direct visualization of the vessel through a transparentback window of the actuation apparatus, and the time of collapse ismanually controlled and recorded. According to an automatic arrangement,an optical detection system is configured so that, when the blood streamis no longer visible, there is a change in a reflected light beam in thesame way as described above for tonometry, and consequently, thepressure for collapse is identifiable automatically. The end pointmarking in both situations is the disappearance of the blood stream, onedetected by the operator's vision and the other detected by an opticaldetection system. Preferably, in both cases, the contact device isdesigned in a way to fit the average curvature of the sclera and themovable central piece, which can be a rigid or flexible material, isused to compress the vessel.

The present invention may also be used to provide real-time recording ofintraocular pressure. A built-in single chip microprocessor can be maderesponsive to the intraocular pressure measurements over time and can beprogrammed to create and display a curve relating pressure to time. Therelative position of the movable central piece can be detected, asindicated above, using an optical detection system and the detectedposition in combination with information regarding the amount of currentflowing through the coil of the actuation apparatus can be rapidlycollected and analyzed by the microprocessor to create theaforementioned curve.

It is understood that the use of a microprocessor is not limited to thearrangement wherein curves are created. In fact, microprocessortechnology may be used to create at least the aforementioned calculationunit 10 of the present invention. A microprocessor preferably evaluatesthe signals and the force that is applied. The resulting measurementscan be recorded or stored electronically in a number of ways. Thechanges in current over time, for example, can be recorded on astrip-chart recorder. Other methods of recording and storing the datacan be employed. Logic microprocessor control technology can also beused in order to better evaluate the data.

Still other uses of the present invention relate to evaluation ofpressure in deformable materials in industry and medicine. One suchexample is the use of the present invention to evaluate soft tissue,such as organs removed from cadavers. Cadaver dissection is afundamental method of learning and studying the human body. Thedeformability of tissues such as the brain, liver, spleen, and the like,can be measured using the present invention and the depth of indentationcan be evaluated. In this regard, the contact device of the presentinvention can be modified to fit over the curvature of an organ. Whenthe movable central piece rests upon a surface, it can be actuated toproject into the surface a distance which is inversely proportional tothe tension of the surface and rigidity of the surface to deformation.The present invention can also be used to evaluate and quantify theamount of cicatrization, especially in burn scar therapy. The presentinvention can be used to evaluate the firmness of the scar in comparisonto normal skin areas. The scar skin tension is compared to the value ofnormal skin tension. This technique can be used to monitor the therapyof patients with burn scars allowing a numerical quantification of thecourse of cicatrization. This technique can also be used as an earlyindicator for the development of hypertrophic (thick and elevated)scarring. The evaluation of the tissue pressure and deformability in avariety of conditions such as: a) lymphoedema b) post-surgical effects,such as with breast surgery, and c) endoluminal pressures of holloworgans, is also possible with the apparatus. In the above cases, thepiston-like arrangement provided by the contact device does not have tobe placed in an element that is shaped like a contact lens. To thecontrary, any shape and size can be used, with the bottom surfacepreferably being flat and not curved like a contact lens.

Yet another use of the present invention relates to providing a bandagelens which can be used for extended periods of time. Glaucoma andincreased intraocular pressure are leading causes for rejection ofcorneal transplants. Many conventional tonometers in the market areunable to accurately measure intraocular pressure in patients withcorneal disease. For patients with corneal disease and who have recentlyundergone corneal transplant, a thinner and larger contact device isutilized and this contact device can be used for a longer period oftime. The device also facilitates measurement of intraocular pressure inpatients with corneal disease which require wearing of contact lenses aspart of their treatment.

The present invention may also be modified to non-invasively measureinfant intracranial pressure, or to provide instantaneous and continuousmonitoring of blood pressure through an intact wall of a blood vessel.The present invention may also be used in conjunction with a digitalpulse meter to provide synchronization with the cardiac cycle. Also, byproviding a contact microphone, arterial pressure can be measured. Thepresent invention may also be used to create a dual tonometerarrangement in one eye. A first tonometer can be defined by the contactdevice of the present invention applied over the cornea, as describedabove. The second tonometer can be defined by the previously mentionedcontact device which is modified for placement on the temporal sclera.In using the dual tonometer arrangement, it is desirable to permitlooking into the eye at the fundus while the contact devices are beingactuated. Accordingly, at least the movable central piece of the contactdevice placed over the cornea is preferably transparent so that thefundus can be observed with a microscope.

Although the foregoing illustrated embodiments of the contact devicegenerally show only one movable central piece 16 in each contact device2, it is understood that more than one movable central piece 16 can beprovided without departing from the scope and spirit of the presentinvention. Preferably, the multiple movable central pieces 16 would beconcentrically arranged in the contact device 2, with at least one ofthe flexible membranes 14 interconnecting the concentrically arrangedmovable central pieces 16. This arrangement of multiple movable centralpieces 16 can be combined with any of the aforementioned features toachieve a desired overall combination.

Although the foregoing preferred embodiments include at least onemagnetically actuated movable central piece 16, it is understood thatthere are many other techniques for actuating the movable central piece16. Sound or ultrasound generation techniques, for example, can be usedto actuate the movable central piece. In particular, the sonic orultrasonic energy can be directed to a completely transparent version ofthe movable central piece which, in turn, moves in toward the cornea inresponse to the application of such energy.

Similarly, the movable central piece may be provided with means forretaining a static electrical charge. In order to actuate such a movablecentral piece, an actuation mechanism associated therewith would createan electric field of like polarity, thereby causing repulsion of themovable central piece away from the source of the electric field.

Other actuation techniques, for example, include the discharge of fluidor gas toward the movable central piece, and according to a lessdesirable arrangement, physically connecting the movable central pieceto a mechanical actuation device which, for example, maybe motor drivenand may utilize a strain gauge.

Alternatively, the contact device may be eliminated in favor of amovable central piece in an actuation apparatus. According to thisarrangement, the movable central piece of the actuation apparatus may beconnected to a slidable shaft in the actuation apparatus, which shaft isactuated by a magnetic field or other actuation means. Preferably, aphysician applies the movable central piece of the actuation apparatusto the eye and presses a button which generates the magnetic field.This, in turn, actuates the shaft and the movable central piece againstthe eye. Preferably, the actuation apparatus, the shaft, and the movablecentral piece of the actuation apparatus are appropriately arranged withtransparent portions so that the inside of the patient's eye remainsvisible during actuation.

Any of the above described detection techniques, including the opticaldetection technique, can be used with the alternative actuationtechniques.

Also, the movable central piece 16 may be replaced by an inflatablebladder (not shown) disposed of the substantially rigid annular member12. When inflated, the bladder extends out of the hole in thesubstantially rigid annular member 12 and toward the cornea.

Similarly, although some of the foregoing preferred embodiments utilizean optical arrangement for determining when the predetermined amount ofapplanation has been achieved, it is understood that there are manyother techniques for determining when applanation occurs. The contactdevice, for example, may include an electrical contact arranged so as tomake or break an electrical circuit when the movable central piece movesa distance corresponding to that which is necessary to produceapplanation. The making or breaking of the electrical circuit is thenused to signify the occurrence of applanation.

It is also understood that, after applanation has occurred, the timewhich it takes for the movable central piece 16 to return to thestarting position after termination of the actuating force will beindicative of the intraocular pressure when the intraocular pressure ishigh, the movable central piece 16 returns more quickly to the startingposition. Similarly, for lower intraocular pressures, it takes longerfor the movable central piece 16 to return to its starting position.Therefore, the present invention can be configured to also consider thereturn time of the movable central piece 16 in determining the measuredintraocular pressure.

As indicated above, the present invention may be formed with atransparent central portion in, the contact device. This transparentcentral portion advantageously permits visualization of the inside ofthe eye (for example, the optic nerve) while the intraocular pressure isartificially increased using the movable central piece. Some of theeffects of increased intraocular pressure on the optic nerve, retina,and vitreous are therefore readily observable through the presentinvention, while intraocular pressure is measured simultaneously.

With reference to FIGS. 21 and 22, although the foregoing examplesdescribe placement of the contact device 2 on the cornea, it isunderstood that the contact device 2 of the present invention may beconfigured with a quasi-triangular shape (defined by the substantiallyrigid annular member) to facilitate placement of the contact device 2 onthe sclera of the eye.

With reference to FIGS. 23 and 24, the contact device 2 of the presentinvention may be used to measure episcleral venous pressure. Preferably,when episcleral venous pressure is to be measured, the movable centralpiece 6 has a transparent centrally disposed frustoconical projection16P. The embodiment illustrated FIG. 24 advantageously permitsvisualization of the subject in through at least the transparent centralportion of the movable central piece 16.

Furthermore, as indicated above, the present invention may also be usedto measure pressure in other parts of the body (for example, scarpressure in the context of plastic surgery) or on surfaces of variousobjects. The contact device of the present invention, therefore, is notlimited to the corneal-conforming curved shape illustrated in connectionwith the exemplary embodiments, but rather may have various other shapesincluding a generally flat configuration.

Alternative Embodiment Actuated by Closure of the Eye Lid

With reference to FIGS. 25-31, an alternative embodiment of the systemwill now be described. The alternative apparatus and method uses theforce and motion generated by the eye lid during blinking and/or closureof the eyes to act as the actuation apparatus and activate at least onetransducer 400 mounted in the contact device 402 when the contact device402 is on the cornea. The method and device facilitate the remotemonitoring of pressure and other physiological events by transmittingthe information through the eye lid tissue, preferably viaelectromagnetic waves. The information transmitted is recovered at areceiver 404 remotely placed with respect to the contact device 402,which receiver 404 is preferably mounted in the frame 408 of a pair ofeye glasses. This alternative embodiment also facilitates utilization offorceful eye lid closure to measure outflow facility. The transducer ispreferably a microminiature pressure-sensitive transducer 400 thatalters a radio frequency signal in a manner indicative of physicalpressure exerted on the transducer 400.

Although the signal response from the transducer 400 can be communicatedby cable, it is preferably actively or passively transmitted in awireless manner to the receiver 404 which is remotely located withrespect to the contact device 402. The data represented by the signalresponse of the transducer 400 can then be stored and analyzed.Information derived from this data can also be communicated by telephoneusing conventional means.

According to the alternative embodiment, the apparatus comprises atleast one pressure-sensitive transducer 400 which is preferablyactivated by eye lid closure and is mounted in the contact device 402.The contact device 402, in turn, is located on the eye. In order tocalibrate the system, the amount of motion and squeezing of the contactdevice 402 during eye lid motion/closure is evaluated and calculated. Asthe upper eyelid descends during blinking, it pushes down and squeezesthe contact device 402, thereby forcing the contact device 402 toundergo a combined sliding and squeezing motion.

Since normal individuals involuntarily blink approximately every 2 to 10seconds, this alternative embodiment of the present invention providesfrequent actuation of the transducer 400. In fact, normal individualswearing a contact device 402 of this type will experience an increase inthe number of involuntary blinks, and this, in turn, tends to providequasi-continuous measurements. During sleep or with eyes closed, sincethere is uninterrupted pressure by the eye lid, the measurements can betaken continuously.

As indicated above, during closure of the eye, the contact device 402undergoes a combined squeezing and sliding motion caused by the eye lidduring its closing phase. Initially the upper eye lid descends from theopen position until it meets the upper edge of the contact device 402,which is then pushed downward by approximately 0.5 mm to 2 mm. Thisdistance depends on the type of material used to make the structure 412of the contact device 402 and also depends on the diameter thereof.

When a rigid structure 412 is used, there is little initial overlapbetween the lid and the contact device 402. When a soft structure 412 isused, there is a significant overlap even during this initial phase ofeye lid motion. After making this initial small excursion the contactdevice 402 comes to rest, and the eye lid then slides over the outersurface of the contact device 402 squeezing and covering it. It isimportant to note that if the diameter of the structure 412 is greaterthan the lid aperture or greater than the corneal diameter, the upperlid may not strike the upper edge of the contact device 402 at thebeginning of a blink.

The movement of the contact device 402 terminates approximately at thecorneo-scleral junction due to a slope change of about 13 degrees in thearea of intersection between cornea (radius of 9 mm) and sclera (radiusof 11.5 mm). At this point the contact device 402, either with a rigidor soft structure 412, remains immobile and steady while the eye lidproceeds to cover it entirely.

When a rigid structure 412 is used, the contact device 402 is usuallypushed down 0.5 mm to 2 mm before it comes to rest. When a softstructure 412 is used, the contact device 402 is typically pushed down0.5 mm or less before it comes to rest. The larger the diameter of thecontact device 402, the smaller the motion, and when the diameter islarge enough there may be zero vertical motion. Despite thesedifferences in motion, the squeezing effect is always present, therebyallowing accurate measurements to be taken regardless of the size of thestructure 412. Use of a thicker structure 412 or one with a flattersurface results in an increased squeezing force on the contact device402.

The eye lid margin makes a re-entrant angle of about 35 degrees withrespect to the cornea. A combination of forces, possibly caused by thecontraction of the muscle of Riolan near the rim of the eye lid and ofthe orbicularis muscle, are applied to the contact device 402 by the eyelid. A horizontal force (normal force component) of approximately 20,000to 25,000 dynes and a vertical force (tangential force component) ofabout 40 to 50 dynes is applied on the contact device 402 by the uppereye lid. In response to these forces, the contact device 402 moves bothtoward the eye and tangentially with respect thereto. At the moment ofmaximum closure of the eye, the tangential motion and force are zero andthe normal force and motion are at a maximum.

The horizontal lid force of 20,000 to 25,000 dynes pressing the contactdevice 402 against the eye generates enough motion to activate thetransducer 400 mounted in the contact device 402 and to permitmeasurements to be performed. This eye lid force and motion toward thesurface of the eye are also capable of sufficiently deforming many typesof transducers or electrodes which can be mounted in the contact device402. During blinking, the eye lids are in full contact with the contactdevice 402 and the surface of each transducer 400 is in contact with thecornea/tear film and/or inner surface of the eye lid.

The microminiature pressure-sensitive radio frequency transducer 400preferably consists of an endoradiosonde mounted in the contact device402 which, in turn, is preferably placed on the cornea and is activatedby eye lid motion and/or closure. The force exerted by the eye lid onthe contact device 402, as indicated above, presses it against thecornea.

According to a preferred alternative embodiment illustrated in FIG. 26,the endoradiosonde includes two opposed matched coils which are placedwithin a small pellet. The flat walls of the pellet act as diaphragmsand are attached one to each coil such that compression of the diaphragmby the eye lid brings the coils closer to one another. Since the coilsare very close to each other, minimal changes in their separation affecttheir resonant frequency.

A remote grid-dip oscillator 414 maybe mounted at any convenientlocation near the contact device 402, for example, on a hat or cap wornby the patient. The remote grid-dip oscillator 414 is used to induceoscillations in the transducer 400. The resonant frequency of theseoscillations is indicative of intraocular pressure.

Briefly, the contact of the eye lid with the diaphragms forces a pair ofparallel coaxial archimedean-spiral coils in the transducer 400 to movecloser together. The coils constitute a high-capacitance distributedresonant circuit having a resonant frequency that varies according torelative coil spacing. When the coils approach one another, there is anincrease in the capacitance and mutual inductance, thereby lowering theresonant frequency of the configuration. By repeatedly scanning thefrequency of an external inductively coupled oscillating detector of thegrid-dip type, the electromagnetic energy which is absorbed by thetransducer 400 at its resonance is sensed through the intervening eyelid tissue.

Pressure information from the transducer 400 is preferably transmittedby radio link telemetry. Telemetry is a preferred method since it canreduce electrical noise pickup and eliminates electric shock hazards. FM(frequency modulation) methods of transmission are preferred since FMtransmission is less noisy and requires less gain in the modulationamplifier, thus requiring less power for a given transmission strength.FM is also less sensitive to variations in amplitude of the transmittedsignal.

Several other means and transducers can be used to acquire a signalindicative of intraocular pressure from the contact device 402. Forexample, active telemetry using transducers which are energized bybatteries or using cells that can be recharged in the eye by an externaloscillator, and active transmitters which can be powered from a biologicsource can also be used.

The preferred method to acquire the signal, however, involves at leastone of the aforementioned passive pressure sensitive transducers 400which contain no internal power source and operate using energy suppliedfrom an external source to modify the frequency emitted by the externalsource. Signals indicative of intraocular ocular pressure are based onthe frequency modification and are transmitted to remote extra-ocularradio frequency monitors. The resonant frequency of the circuit can beremotely sensed, for example, by a grid-dip meter.

In particular, the grip-dip meter includes the aforementioned receiver404 in which the resonant frequency of the transducer 400 can bemeasured after being detected by external induction coils 415 mountednear the eye, for example, in the eyeglass frames near the receiver orin the portion of the eyeglass frames which surround the eye. The use ofeyeglass frames is especially practical in that the distance between theexternal induction coils 415 and the radiosonde is within the typicalworking limits thereof. It is understood, however, that the externalinduction coils 415, which essentially serve as a receiving antenna forthe receiver 404 can be located any place that minimizes signalattenuation. The signal from the external induction coils 415 (orreceiving antenna) is then received by the receiver 404 foramplification and analysis.

When under water, the signal may be transmitted using modulated soundsignals because sound is less attenuated by water than are radio waves.The sonic resonators can be made responsive to changes in temperatureand voltage.

Although the foregoing description includes some preferred methods anddevices in accordance with the alternative embodiment of the presentinvention, it is understood that the invention is not limited to thesepreferred devices and methods. For example, many other types ofminiature pressure sensitive radio transmitters can be used and mountedin the contact device, and any microminiature pressure sensor thatmodulates a signal from a radio transmitter and sends the modulatedsignal to a nearby radio receiver can be used.

Other devices such as strain gauges, preferably piezoelectric pressuretransducers, can also be used on the cornea and are preferably activatedby eye lid closure and blinking. Any displacement transducer containedin a distensible case also can be mounted in the contact device. Infact, many types of pressure transducers can be mounted in and used bythe contact device. Naturally, virtually any transducer that cantranslate the mechanical deformation into electric signals is usable.

Since the eye changes its temperature in response to changes inpressure, a pressure-sensitive transducer which does not require motionof the parts can also be used, such as a thermistor. Alternatively, thedielectric constant of the eye, which also changes in response topressure changes, can be evaluated to determine intraocular pressure. Inthis case, a pressure-sensitive capacitor can be used. Piezoelectric andpiezo-resistive transducers, silicon strain gauges, semiconductordevices and the like can also be mounted and activated by blinkingand/or closure of the eyes.

In addition to providing a novel method for performing singlemeasurements, continuous measurements, and self-measurement ofintraocular pressure during blinking or with the eyes closed, theapparatus can also be used to measure outflow facility and otherphysiological parameters. The inventive method and device offer a uniqueapproach to measuring outflow facility in a physiological manner andundisturbed by the placement of an external weight on the eye.

In order to determine outflow facility in this fashion, it is necessaryfor the eye lid to create the excess force necessary to squeeze fluidout of the eye. Because the present invention permits measurement ofpressure with the patient's eyes closed, the eye lids can remain closedthroughout the procedure and measurements can be taken concomitantly. Inparticular, this is accomplished by forcefully squeezing the eye lidsshut. Pressures of about 60 mm Hg will occur, which is enough to squeezefluid out of the eye and thus evaluate outflow facility. The intraocularpressure will decrease over time and the decay in pressure with respectto time correlates to the outflow facility. In normal individuals, theintraocular fluid is forced out of the eye with the forceful closure ofthe eye lid and the pressure will decrease accordingly; however, inpatients with glaucoma, the outflow is compromised and the eye pressuretherefore does not decrease at the same rate in response to the forcefulclosure of the eye lids. The present system allows real time andcontinuous measurement of eye pressure and, since the signal can betransmitted through the eye lid to an external receiver, the eyes canremain closed throughout the procedure.

Telemetry systems for measuring pressure, electrical changes,dimensions, acceleration, flow, temperature, bioelectric activity,chemical reactions, and other important physiological parameters andpower switches to externally control the system can be used in theapparatus of the invention. The use of integrated circuits and technicaladvances occurring in transducer, power source, and signal processingtechnology allow for extreme miniaturization of the components which, inturn, permits several sensors to be mounted in one contact device, asillustrated for example in FIG. 28.

Modem resolutions of integrated circuits are in the order of a fewmicrons and facilitate the creation of very high density circuitarrangements. Preferably, the modem techniques of manufacturingintegrated circuits are exploited in order to make electronic componentssmall enough for placement on the eyeglass frame 408. The receiver 404,for example, may be connected to various miniature electronic components418, 419, 420, as schematically illustrated in FIG. 31, capable ofprocessing, storing, and even displaying the information derived fromthe transducer 400.

Radio frequency and ultrasonic micro-circuits are available and can bemounted in the contact device for use thereby. A number of differentultrasonic and pressure transducers are also available and can be usedand mounted in the contact device. It is understood that furthertechnological advances will occur which will permit further applicationsof the apparatus of the invention.

The system may further comprise a contact device for placement on thecornea and having a transducer capable of detecting chemical changes inthe tear film. The system may further include a contact device forplacement on the cornea and having a microminiature gas-sensitive radiofrequency transducer (e.g., oxygen-sensitive). A contact device having amicrominiature blood velocity-sensitive radio frequency transducer mayalso be used for mounting on the conjunctiva and is preferably activatedby eye lid motion and/or closure of the eye lid.

The system also may comprise a contact device in which a radio frequencytransducer capable or measuring the negative resistance of nerve fibersis mounted in the contact device which, in turn, is placed on the corneaand is preferably activated by eye lid motion and/or closure of the eyelid. By measuring the electrical resistance, the effects ofmicroorganisms, drugs, poisons and anesthetics can be evaluated.

The system of the present invention may also include a contact device inwhich a microminiature radiation-sensitive radio frequency transducer ismounted in the contact device which, in turn, is placed on the corneaand is preferably activated by eye lid motion and/or closure of the eyelid.

In any of the foregoing embodiments having a transducer mounted in thecontact device, a grid-dip meter can be used to measure the frequencycharacteristics of the tuned circuit defined by the transducer.

Besides using passive telemetry techniques as illustrated by the use ofthe above transducers, active telemetry with active transmitters and amicrominiature battery mounted in the contact device can also be used.

The contact device preferably includes a rigid or flexible transparentstructure 412 in which at least one of the transducers 400 is mounted inhole(s) formed in the transparent structure 412. Preferably, thetransducers 400 is/are positioned so as to allow the passage of lightthrough the visual axis. The structure 412 preferably includes an innerconcave surface shaped to match an outer surface of the cornea.

As illustrated in FIG. 29, a larger transducer 400 can be centrallyarranged in the contact device 402, with a transparent portion 416therein preserving the visual axis of the contact device 402.

The structure 412 preferably has a maximum thickness at the center and aprogressively decreasing thickness toward a periphery of the structure412. The transducers is/are preferably secured to the structure 412 sothat the anterior side of each transducer 400 is in contact with theinner surface of the eye lid during blinking and so that the posteriorside of each transducer 400 is in contact with the cornea, thus allowingeye lid motion to squeeze the contact device 402 and its associatedtransducers 400 against the cornea.

Preferably, each transducer 400 is fixed to the structure 412 in such away that only the diaphragms of the transducers experience motion inresponse to pressure changes. The transducers 400 may also have anysuitable thickness, including matching or going beyond the surface ofthe structure 412.

The transducers 400 may also be positioned so as to bear against onlythe cornea or alternatively only against the inner surface of the eyelid. The transducers 400 may also be positioned in a protruding waytoward the cornea in such a way that the posterior part flattens aportion of the cornea upon eye lid closure. Similarly, the transducers400 may also be positioned in a protruding way toward the inner surfaceof the eye lid so that the anterior part of the transducer 400 ispressed by the eye lid, with the posterior part being covered by aflexible membrane allowing interaction with the cornea upon eye lidclosure.

A flexible membrane of the type used in flexible or hydrogel lenses mayencase the contact device 402 for comfort as long as it does notinterfere with signal acquisition and transmission. Although thetransducers 400 can be positioned in a manner to counterbalance eachother, as illustrated in FIG. 28, it is understood that a counter weightcan be used to maintain proper balance.

FIG. 32 illustrates the contact device 500 placed on the surface of theeye with mounted sensor 502, transmitter 504, and power source 506 whichare connected by fine wire 508 (shown only partially extending fromsensor 502 and from transmitter 504), encased in the contact device. Thecontact device shown measures approximately 24 mm in its largestdiameter with its corneal portion 510 measuring approximately 11 mm indiameter with the remaining 13 mm subdivided between 8 mm of a portion512 under the upper eyelid 513 and 5 mm of a portion 514 under the lowereyelid 515. The contact device in FIG. 32 has microprotuberances 516 inits surface which increases friction and adhesion to the conjunctivaallowing diffusion of tissue fluid from the blood vessels into thesensor selective membrane surface 518. The tissue fluid goes throughmembranes in the sensor and reaches an electrode 520 with generation ofcurrent proportional to the amount of analyte found in the tear fluid522 moving in the direction of arrows 524. A transmitter 504transmitting a modulated signal 526 to a receiver 528 with the signal526 being amplified and filtered in amplifier and filter 529, decoded indemultiplexes 530, processed in CPU 532, displayed at monitor 534, andstored in memory 536.

The contact device 540 shown in FIG. 33A includes two sensors, onesensor 542 for detection of glucose located in the main body 544 of thecontact device and a cholesterol sensor 546 located on a myoflange 548of the contact device 540. Formning part of the contact device is aheating electrode 550 and a power source 552 next to the cholesterolsensor 546 with the heating electrode 550 increasing the localtemperature with subsequent translation of fluid in the direction ofarrows 553 toward the cholesterol sensor 546.

In one embodiment the cholesterol sensor shown in FIG. 33C includes anouter selectively permeable membrane 554, and mid-membranes 556, 558with immobilized cholesterol esterase and cholesterol oxidase enzymesand an inner membrane 560 permeable to hydrogen peroxide. The externalmembrane 554 surface has an area preferably no greater than 300 squaremicrometers and an overall thickness of the multiple membrane layers isin the order of 30-40 micrometers. Covered by the inner membrane are aplatinum electrode 562 and two silver electrodes 564 measuring 0.4 mm(platinum wire) and 0.15 mm (silver wire). Fine wires 566,568 connectthe cholesterol sensor 546 to the power source 552 and transmitter 570.The glucose sensor 542 includes a surrounding irregular external surface572 to increase friction with the sensor connected by fine wires 574,576 to the power source 578 and transmitter 570. The power source 578 isconnected to the sensor in order to power the sensor 542 for operation.

The transmitter includes integrated circuits for receiving andtransmitting the data with the transmitters being of ultra denseintegrated hybrid circuits measuring approximately 500 microns in itslargest dimension. The corneal tissue fluid diffuses in the direction ofarrows 580 toward the glucose sensor 542 and reaches an outer membrane582 permeable to glucose and oxygen followed by an immobilized glucoseoxidase membrane 584 and an inner membrane 586 permeable to hydrogenperoxide. The tissue fluid then reaches the one platinum 588 and twosilver 590 electrodes, generating a current proportional to theconcentration of glucose. The dimensions of the glucose sensor aresimilar to the dimensions of the cholesterol sensor.

FIG. 34 illustrates by, a block diagram, examples of signals obtainedfor measuring various biological variables such as glucose 600,cholesterol 602 and oxygen 604 in the manner as exemplified in FIGS.33A-33C. A glucose signal 606, a cholesterol signal 608 and an oxygensignal 610 are generated by transducers or sensors as shown in FIGS. 33Band 33C. The signals are transmitted to a multiplexer 612 whichtransmits the signals as a coded signal by wire 614 to a transmitter616. A coded and modulated signal is transmitted, as represented by line618, by radio, light, sound, wire telephone or the like with noisesuppression to a receiver 620. The signal is then amplified and filteredat amplifier and filter 622. The signal passes through a demultiplexer624 and the separated signals are amplified at 626, 628, 630,respectively and transmitted and displayed at display 632 of a CPU andrecorded for transmission by modem 634 to an intensive care unit, forexample.

FIGS. 35A-35C illustrate an intelligent contact lens being activated byclosure of the eyelids with subsequent increased diffusion of bloodcomponents to the sensor. During movement of the eye lids from theposition shown in FIG. 35C to the position shown in FIG. 35A by blinkingand/or closure of the eye, a combination of forces are applied to thecontact device 636 by the eyelid with a horizontal force (normal forcecomponent) of approximately 25,000 dynes which causes an intimateinteraction between the contact device and the surface of the eye with adisruption of the lipid layer of the tear film allowing directinteraction of the outer with the palpebral conjunctiva as well as adirect interaction of the inner surface of the contact device with theaqueous layer of the tear film and the epithelial surface of the corneaand bulbar conjunctiva. Blinking promotes a pump system which extractsfluid from the supero-temporal corner of the eye and delivery of fluidto the puncta in the infero-medial corner of the eye creating acontinuous flow which bathes the contact device. During blinking, theclose interaction with the palpebral conjunctiva, bulbar conjunctiva,and cornea, the slightly rugged surface of the contact device createsmicrodisruption of the blood barrier and of the epithelial surface withtransudation and increased flow of tissue fluid toward the surface ofthe contact device. The tear fluid then diffuses through the selectivelypermeable membranes located on the surface of the contact device 636 andsubsequently reaching the electrodes of the sensor 638 mounted in thecontact device. In the preferred embodiment for glucose measurement,glucose and oxygen flow from the capillary vessels 640 toward aselectively permeable outer membrane and subsequently reach amid-membrane with immobilized glucose oxidase enzyme. At this layer ofimmobilized glucose oxidase enzyme, a enzymatic oxidation of glucose inthe presence of the enzyme oxidase and oxygen takes place with theformation of hydrogen peroxide and gluconic acid. The hydrogen peroxidethen diffuses through an inner membrane and reaches the surface of aplatinum electrode and it is oxidized on the surface of the workingelectrode creating a measurable electrical current. The intensity of thecurrent generated is proportional to the concentration of hydrogenperoxide which is proportional to the concentration of glucose. Theelectrical current is subsequently converted to a frequency audio signalby a transmitter mounted in the contact device with signals beingtransmitted to a remote receiver using preferably electromagnetic energyfor subsequent amplification, decoding, processing, analysis, anddisplay.

In FIGS. 36A through 36J, various shapes of contact devices are shownfor use in different situations. In FIG. 36A, a contact device 642 isshown of an elliptical, banana or half moon shape for placement underthe upper or lower eye lid. FIGS. 36B and 36C show a contact device 644having, in side view a wide base portion 646 as compared to an upperportion 648. FIG. 36D shows a contact device 650 having a truncated lensportion 652.

In FIGS. 36E and 36F, the contact device 654 is shown in side view inFIG. 36E and includes a widened base portion 656 which as shown in FIG.36F is of a semi-truncated configuration.

FIG. 36G shows a contact device 658, having a corneal portion 650 and ascleral portion 652. In FIG. 36H, an oversized contact device 664,includes a corneal portion 666 and a scleral portion 668.

A more circular shaped contact device 670 is shown in FIG. 36I having acorneal-scleral lens 672.

The contact device 674 shown in FIG. 36J is similar to the ones shown inFIGS. 32, 33A, 35A and 35C. The contact device includes a main bodyportion 676 with upper myoflange or minus carrier 678 and lowermyoflange or minus carrier 680.

In FIG. 37A, an upper contact device 682 is placed under an upper eyelid 684. Similarly, a lower contact device 686 is placed underneath alower eye lid 688. Upper contact device 682 includes an oxygensensor/transmitter 690 and a glucose transmitter 692. Similarly, thelower contact device includes a temperature sensor transmitter 694 and apH sensor/transmitter 696.

Each of these four sensors outputs a signal to respective receivers 698,700,702 and 704, for subsequent display in CPU displays 706, 708, 710,712, respectively. The CPUs display an indication of a sensed oxygenoutput 714, temperature output 716, pH output 718 and glucose output720.

In FIG. 37B, a single contact device 722, in an hour glass shape,includes an upper sodium sensor/transmitter 724 and a lower potassiumsensor/transmitter 726. The two sensors send respective signals toreceivers 728 and 730 for display in CPUs 732, 734 for providing asodium output indicator 736 and a potassium output indicator 738.

In FIG. 38A, a contact device 740 is shown which may be formed of anannular band 742 so as to have a central opening with the openingoverlying a corneal portion or if the contact device includes a cornealportion, the corneal portion lays on the surface of the cornea. Limitedto annular band 742 is a sensor 744 positioned on the scleral portion ofthe contact device so as to be positioned under an eye lid. The sensoris connected by wires 746 a, 746 b to transmitter 748 which is incommunication with the power source 750 by wires 752 a, 752 b. Theintelligent contact lens device 740 is shown in section in FIG. 38B withthe power source 750 and sensor 744 located on opposite ends of thecontact device on the scleral portion of the contact device.

FIG. 39A schematically illustrates the flow of tear fluid as illustratedby arrows 754 from the right lacrimal gland 756 across the eye to thelacrimal punctum 758 a and 758. Taking advantage of the flow of tearfluid, in FIG. 39B, a contact device 760 is positioned in the lowercul-de-sac 762 beneath the lower eye lid 764 so that a plurality ofsensors 764 a, 764 b and 764 c in wire communication with a power source766 and transducer 768 can be connected by a wire 770 to an externaldevice. The flow of tear fluid from the left lacrimal gland 762 to thelacrimal punctum 764 a and 764 b is taken advantage of to produce areading indicative of the properties to be detected by the sensors.

In FIG. 40A, a contact device 772 is positioned in the cul-de-sac 774 ofthe lower eye lid 776. The contact device includes a needle-type glucosesensor 778 in communication with a transmitter 780 and a power source782. A signal 782 is transmitted to a receiver, demultiplexer andamplifier 784 for transmission to a CPU and modem 786 and subsequenttransmission over a public communication network 788 for receipt andappropriate action at an interface 790 of a hospital network.

In FIG. 40B, a similar arrangement to that shown in FIG. 40A is usedexcept the glucose sensor 792 is a needle type sensor with a curvedshape so as to be placed directly against the eye lid. The sensor 792 issilicone coated or encased by coating with silicone for comfortable wearunder the eye lid 794. Wires 796 a and 796 b extend from under the eyelid and are connected to an external device. The sensor 792 is placed indirect contact with the conjunctiva with signals and power sourceconnected by wires to external devices.

FIG. 41 shows an oversized contact device 798 including sensors 800 a,800 b, 800 c and the scleral portion of the contact device to bepositioned under the upper eye lid. In addition, sensors 802 a, 802 b,802 c are to be positioned under the lower eye lid in contact with thebulbar and/or palpebral conjunctiva. In addition, sensors 804 a-d arelocated in the corneal portion in contact with the tear film over thecornea.

FIG. 42A shows a contact device 806 having a sensor 808 and atransmitter 810 in position, at rest, with the eye lids open. However,in FIG. 42B, when the eye lids move towards a closed position, and theindividual is approaching a state of sleep, the Bell phenomenon willmove the eye and therefore the contact device upward in the direction ofarrows 812. The pressure produced from the eye lid as the contact devicemoves up, will produce a signal 814 from the sensor 808 which istransmitted to a receive 816. The signal passes through an amplifier andfilter 818 to a demultiplexer 820 for activation of an alarm circuit 822and display of data at 824. The alarm should be sufficient to wake adozing driver or operator of other machinery to alert the user of signsof somnolence.

In FIG. 43, a heat stimulation transmission device 825 for externalplacement on the surface of the eye is shown for placement on thescleral and corneal portions of the eye. The device 825 includes aplurality of sensors 826 spaced across the device 825. With reference toFIG. 44, the device 825 includes heating elements 828 a-c, a thermistor830, an oxygen sensor 832, and a power source 834. Signals generated bythe sensors are transmitted by transmitter 836 to hardware 838 whichprovides an output representative of a condition detected by thesensors.

In FIG. 46, an annular band 840 includes a plurality of devices 842 a-e.The annular band shaped heat stimulation transmission device 840 can beused externally or internally by surgical implication in any part of thebody. Another surgically implantable device 844 is shown in FIG. 46. Inthis example, the heat stimulation transmission device 844 is implantedbetween eye muscles 846, 848. Another example of a surgicallyimplantable heat stimulation transmission device 850 is shown in FIG.47, having four heating elements 852, a temperature sensor 854 and anoxygen sensor 856, with a power source 858 and a transmitter 860 fortransmitting signal 852.

FIGS. 48, 49 and 51 through 53 illustrate the use of an overheatingtransmission device, as shown in FIG. 50, for the destruction of tumorcells after the implantation of the overheating transmission device bysurgery. As shown in FIG. 50, the overheating transmission device 864includes a plurality of heating elements 866 a, 866 b, 866 c, atemperature sensor 868, a power source 870 which is inductivelyactivated and a transmitter 872 for transmitting a signal 874. Byactivation of the device 864, an increase in temperature results in theimmediately adjacent area. This can cause the distruction of tumor cellsfrom a remote location.

In FIG. 48, the device 864 is located adjacent to a brain tumor 876. InFIG. 49, the device 864 is located adjacent to a kidney tumor 878.

In FIG. 51, the device 864 is located adjacent to an intraocular tumor880. In FIG. 52, a plurality of devices 864 are located adjacent to alung tumor 882. In FIG. 53, a device 864 is located externally on thebreast, adjacent to a breast tumor 884.

In FIGS. 54A and 54B, a contact device 886 is located on the eye 888.The contact device is used to detect glucose in the aqueous humor byemitting light from light emitting optical fiber 890, which is sensitiveto glucose, as compared to a reference optical fiber light source 892,which is not sensitive to glucose. Two photo detectors 894 a, 894 bmeasure the amount of light passing from the reference optical fiber 892and the emitting optical fiber 890 sensitive to glucose and transmit thereceived signals by wires 896 a, 896 b for analysis.

In FIG. 54C, a glucose detecting contact device 900 is used having apower source 902, an emitting light source 904 sensitive to glucose anda reference light source 906, non-sensitive to glucose. Two photodetectors 908 a and 908 b, provide a signal to a transmitter 910 fortransmission of a signal 912 to a remote location for analysis andstorage.

In FIG. 55A, a contact device 914 is positioned on an eye 916 fordetection of heart pulsations or heart sounds as transmitted to eye 916by the heart 918 as a normal bodily function. A transmitter provides asignal 920 indicative of the results of the heart pulsations or heartsound. A remote alarm device 922 may be worn by the individual. Thedetails of the alarm device are shown in FIG. 55B where the receiver 924receives the transmitted signal 920 and conveys the signal to a displaydevice 926 as well as to an alarm circuit 928 for activation of an alarmif predetermined parameters are exceeded.

In FIG. 56, a contact device. 930 is shown. The contact device includesan ultra sound sensor 932, a power source 934 and a transmitter 936 forconveying a signal 938. The ultra sound sensor 932 is placed on a blood-vessel 940 for measurement of blood flow and blood velocity. The resultof this analysis is transmitted by signal 938 to a remote receiver foranalysis and storage.

In FIG. 57, an oversized contact device 940 includes a sensor 942, apower source 944 and a transmitter 946 for transmitting a signal 948.The sensor 942 is positioned on the superior rectus muscle formeasurement of eye muscle potential. The measured potential istransmitted by signal 948 to a remote receiver for analysis and storage.

In FIG. 58A, a contact device 950 includes a light source 952, a powersource 954, multioptical filter system 956 and a transmitter 958 fortransmission of a signal 960. The light source 952 emits a beam of lightto the optic nerve head 962. The beam of light is reflected on to themultioptical filter system 956 for determination of the angle ofreflection.

As shown in FIG. 58B, since the distance X of separation between themultioptical filter system and the head of the optic nerve 962 remainsconstant as does the separation distance Y between the light source 952and the multoptical filter system 956, a change in the point P which isrepresentative of the head of the optic nerve will cause a consequentchange in the angle of reflection so that the reflected light will reacha different point on the multioptical filter system 956. The change ofthe reflection point on multioptical filter system 956 will create acorresponding voltage change based on the reflection angle. The voltagesignal is transmitted as an audio frequency signal 960 to a remotelocation for analysis and storage.

In FIGS. 59A through 59C, a neuro stimulation transmission device 964 isshown. In FIG. 59A , the device 964 is surgically implanted in the brain966. The device 964 includes microphotodiodes or electrodes 968 and apower source/transmitter 970. The device is implanted adjacent to theoccipital cortex 972.

In FIG. 59B, the device 964 is surgically implanted in the eye 974 on aband 976 including microphotodiodes 978 a, 978 b with a power source 980and a transmitter 982.

In FIG. 59C, the device 964 is externally placed on the eye 974 using anoversized contact device 984 as a corneal scleral lens. The deviceincludes an electrode 986 producing a microcurrent, a microphotodiode orelectrode 988, a power source 990 and a transmitter 992 for transmissionof a signal to a remote location for analysis and storage.

In FIG. 60, a contact device 1000 includes a power source 1002 and afixed frequency transmitter 1004. The transmitter 1004 emits a frequencywhich is received by an orbiting satellite 1006. Upon detection of thefrequency of the signal transmitted by the transmitter 1004, thesatellite can transmit a signal for remote reception indicative of thelocation of the transmitter 1004 and accordingly the exact location ofthe individual wearing the contact device 1000. This would be useful inmilitary operations to constantly monitor the location of all personal.

In FIG. 61, a contact device 1008 is located below the lower eye lid1010. The contact device includes a pressure sensor, an integratedcircuit 1012, connected to an LED drive 1014 and an LED 1016. A powersource 1018 is associated with the device located in the contact device1008.

By closure of the eye 1020 by the eye lids, the pressure sensor 1012would be activated to energize the LED drive and therefore the LED fortransmission of a signal 1020 to a remote photodiode or optical receiver1022 located on a receptor system. The photodiode or optical receiver1022, upon receipt of the signal 1020, can transmit a signal 1024 forturning on or off a circuit. This application has may uses -for thoseindividuals limited in their body movement to only their eyes.

In FIG. 62, a contact device 1026 includes compartments 1028, 1030 whichinclude a chemical or drug which can be dispensed at the location of thecontact device 1026. The sensor 1032 provides an signal indicative of aspecific condition or parameter to be measured. Based upon the resultsof the analysis of this signal, when warranted, by logic circuit 1034, aheater device 1036 can be activated to melt a thread or other closuremember 1038 sealing the compartments 1028, 1030 so as to allow releaseof the chemical or drug contained in the compartments 1028, 1030. Thesystem is powered by power source 1040 based upon the biologicalvariable signal generated as a result of measurement by sensor 1032.

According to the system shown in FIG. 63, a glucose sensor 1042,positioned on the eye 1044, can generate a glucose level signal 1046 toa receiver 1048 associated with an insulin pump 1050 for release ofinsulin into the blood stream 1052. The associated increase in insulinwill again be measured on the eye 1044 by the sensor 1042 so as tocontrol the amount of insulin released by the insulin pump 1050. Aconstant monitoring system is thereby established

In reference to FIG. 64A through 64D there is shown the steps for theexperimental in-vitro testing according to the biological principles ofthe invention. The biological principles of the current inventioninclude the presence of superficially located fenestrated blood vesselsin the conjunctiva allowing tissue fluid to freely flow from the vesselsof the eye for analysis. FIGS. 64A-64D shows the schematic illustrationof the testing of an eye to confirm the location of fenestated vessels.A side view of the eye ball in FIG. 64A shows the conjunctiva 1110 withits vessels 1112 covering both the eye ball 1114 and the eye lid (notshown). A main conjunctival vessel 1116 in the limbal area shown in FIG.64B is then cannulated and fluorescein dye 1118 injected through syringe1119 into the vessel 1116. The dye starts to leak from the fenestratedvessels into the conjunctival space 1120 and surface of the eye 1122 inmid-phase in FIG. 64C. In the late phase (FIG. 64D) there is a massiveleakage 1124 of fluid (fluorescein dye) completely covering the surfaceof the eye due to the presence of superficially located fenestratedvessels.

Another experiment consisted of attaching a glucose oxidase strip to avariety of contact lens materials which were subsequently placed in theeye lid pocket. Blood samples were acquired from non-diabetic subjectsusing whole blood from the tip of the finger. The glucose oxidase enzymedetects the oxidable species present in the eye, in this example, theamount of glucose. The enzymes are coupled to a chromogen which createda color change based on the amount of the analyte (glucose). Acombination of the forces caused by the physiologic muscular activity ofthe orbicularis muscle and muscle of Riolam in the eye lid generating anormal force component of 25,000 dynes acts on the contact device whichpromotes a fluid flux of analyte toward the strip with the subsequentdevelopment of color changes according to the amount of glucose. Fastingplasma concentration of glucose as identified by the contact lens systemof the current invention was 15% higher than whole blood whichcorresponds to the physiologic difference between whole blood glucoseand plasma glucose.

In reference to FIGS. 65A-65F there are shown a series of picturesrelated to in-vivo testing in humans related to the biologicalprinciples of the invention. FIGS. 65A through 65F show an angiogram ofconjunctival blood vessels present on the surface of the eye in a normalhealthy living human subject. The fluorescein dye is injected into thevein of the subject and serial photographs with special illumination andfilters are taken from the surface of the eye. The fluorescein angiogramallows evaluation of the anatomic structure and integrity of bloodvessels as well as their physiologic behavior. Vessels which do not leakkeep the fluorescein dye (seen as white) inside the vessel and appear asstraight lines. Vessels in which there is leakage appear as white linessurrounded by white areas. The white areas represent the fluorescein(white) which left the vessels and is spreading around said bloodvessels. Since there is continuous leakage as the dye reaches theconjunctiva, as time progresses the whole area turns white due to thewidespread and continuous leakage.

FIG. 65A shows a special photograph of the conjunctiva before dye isinjected and the area appears as black. About 15 seconds after the dyeis injected into a vein of a patient, the dye appears in the conjunctivaand starts to fill the conjunctival blood vessels (FIG. 65B). Theinitial filling of few conjunctival vessels is followed by filling ofother vessels after 22 seconds from injection into the vein (FIG. 65C)with progressive leakage of the dye from the conjunctival vesselsforming the fluffy white images around the vessels as filling of vesselsprogresses. After about 30 seconds from the time of injection most ofthe conjunctival vessels begin to leak due to fenestration which isobserved as large white spots. In the late phase, leakage fromconjunctival vessels has increased markedly and reaches the surfaceengulfing the whole conjunctival area as shown in FIG. 65D. Note theintense hyper-fluorescence (white areas) due to leakage that is presentin the conjunctiva.

As with FIG. 68 which shows junction of conjunctiva and skin, FIG. 65Eshows the junction of conjunctiva and cornea. According to thebiological principles of the invention one can easily see the differencebetween vessels with holes (conjunctiva) and vessels without holes(limbal area which is the transition zone between conjunctiva andcornea).

FIG. 65E (photo A) shows an enlarged view of late phase with leakage byconjunctival vessels pointed by the large arrow heads with theconjunctival vessels surrounded by fluffy white areas (=leakage).Contrary to that, when one leaves the conjunctiva the vessels arenon-fenestrated (=no holes) and thus the vessels are observed asstraight white lines without surrounding fluffy white areas. Note thatno leakage is seen from vessels next to the cornea (triple arrows) whichare seen as straight white lines without surrounding white infiltrateswhich means no leakage. Only the conjunctival vessels have fenestration(pores) and leakage of plasma to the surface allowing any analytes andcells present in the eye to be measured.

FIG. 65F (photo B) is an enlarged view showing the complete lack ofleakage by the non-conjunctival blood vessels in the transition betweencornea and conjunctiva which are seen as white straight lines.

Note that these conjunctival vessels leaking fluid (see FIGS. 65C-65E,for example) are part the lining of the eye lid pockets in which toinsert the ICL according to the principles of the present invention. Ittakes about 10 seconds from the time the dye is injected in the veinuntil it reaches the eye. The time correlates with the pumping action ofthe heart. As long as the heart is pumping blood, the conjunctivalvessels will continue to leak allowing the continuous non-invasivemeasurement of blood elements according to the principles of theinvention.

Please note that the conjunctiva is the only superficial organ with suchfenestrated blood vessels. There are areas inside the body such as liverand kidney with fenestrated vessels but for obvious reasons such organsare not accessible for direct non-invasive collection and analysis ofplasma. As previously described the conjunctiva posses all of thecharacteristics needed for non-invasive and broad diagnostics includingfluid and cells for analysis.

FIGS. 66A through 66C are schematic illustrations of an angiogram. FIG.66A shows initial filling of conjunctival vessels 1150 with fluoresceindye. The lower eye lid 1152 with eye lashes 1153 was pulled down toexpose the conjunctival vessels 1150 present in the eye lid pocket 1154.FIGS. 66A through 66C also show the cornea 1156 and pupil 1157 of theeye located above the conjunctival area 1154. FIG. 66B shows mid-phasefilling of conjunctival vessels with leakage represented by large arrowheads 1158. The same figure also shows the lack of leakage in thevessels next to the cornea represented by triple arrows 1160 indicatingthe presence of fenestrated vessels only in the conjunctival area 1154.FIG. 66C shows a late phase of the angiogram of the conjunctival vesselswith almost complete filling of the conjunctival space and surface 1162of the eye in the eyelid pocket 1154. Note that the limbal vessels (notfenestrated, no holes) remain as straight, white lines without leakage.

FIGS. 67A and 67B show a schematic representation of the blood vesselsfound in the conjunctiva with fenestrations (holes) in FIG. 67B comparedto continuous blood vessels (no holes) in FIG. 67A. The fenestratedvessels in the conjunctiva have a discontinuous flat membrane as thin as40 angstroms in thickness and perforated by pores measuring about 600 to700 angstroms. This structural arrangement is of prime importance in thepermeability functions of the vessel, allowing plasma to freely leavethe vessel, and thus any substance and/or cell present in the plasma canbe evaluated according to the principles of the current invention.Contrary to FIG. 67B, FIG. 67A shows continuous walled vessels withcomplete lining of endothelial cells and continuous basement membranewhich does not allow leakage or external flow of blood components. Thosenon-fenestrated vessels are commonly found in the subcutaneous layerdeep under the skin, muscle tissue and connective tissues.

Besides demonstrating that functionally and physiologically theconjunctiva and the eye provides the ideal characteristics fordiagnostics with superficial vessels that leak fluid, the inventor alsodemonstrated from a morphologic standpoint that the conjunctival areaand the eye have the ideal anatomic characteristics for the measurementsaccording to the principles of the present invention. Thus, FIG. 68Ashows a microphotograph depicting the microscopic structure of thejunction (arrow) 1163 between conjunctiva and skin present in the eyelid of a normal adult individual.

This junction 1163 which lies next to the eye lash line is called thelid margin mucosal-cutaneous junction and provides a great illustrationfor comparison between the skin and conjunctiva of the currentinvention. The skin has previously been used for acquiring bloodinvasively as with needles and lasers or minimally invasively as withelectroporation, electroosmosis, and the like. However besides nothaving the superficial fenestrated blood vessels, one can clearly see bythis photograph that the skin is not suitable for such evaluations. Thearrow points to the junction 1163 of skin and conjunctiva. To the leftof the junction arrow 1163 the epithelium of the skin 1164 is seen asthis dark layer of varying thickness in a wave-like shape. Theepithelium of the skin consists of densely organized multiplenon-homogeneous cell layers overlying a thick and continuous tight basecell layer. The dark band is very thick and associated with largeappendages such as a duct of a sebaceous gland 1164 a. The tissue 1164 bunder the black thick superficial band is also thick (dark gray color)because it is composed of dense tissue. The blood vessels 1167 arelocated deep in the subcutaneous area.

Compare now to the conjunctiva on the right of the junction arrow 1163.The epithelium 1165 is so thin that one can barely identify a darkerband superficially located in the photomicrograph. The conjunctiva istransparent and can be illustrated as a very thin cellophane-likematerial with blood vessels 1166. The epithelium of the conjunctiva 1165besides being thin, as shown in FIGS. 68A and 68C is also quitehomogeneous in thickness and becomes even thinner as one moves away fromthe skin (far right). The epithelium of the conjunctiva 1165 consists ofa few loosely organized cell layers overlying a thin, discontinuousbasement membrane with few hemidesmossomes and very wide intercellularspaces. The tissue underneath the thin epithelium of the conjunctiva1165 is whitish (much lighter than the tissue under the thick dark skinepithelium). The reason for the whitish appearance is that theconjunctiva has a very loose substantia propria and loose connectivetissue allowing easy permeation of fluid through those layers. The skinwhich is thick and dense does not provide the same easy passage offluid. The conjunctiva has a voluminous blood supply and the vessels1166 in the conjunctiva are right underneath the surface allowingimmediate reach and permeation to the surface with the adjunct pumpfunction of the eye lid tone. FIG. 68B shows the junction (arrow) 1163in accordance with FIG. 68A. The illustration includes the epithelium1164, and blood vessels 1167 of the skin of the eye lid and bloodvessels 1166 and epithelium 1165 (shown as a single top line) of theconjunctiva. FIG. 68B also includes muscles and ligaments in proximityto the conjunctiva and eye lid pocket such as the inferior tarsal muscle1168, the lower lid retractors 1169, the inferior suspensory ligament ofLockwood 1170, and the inferior rectus muscle 1171. Although, the eyelid has the thinnest skin in the body, the blood vessels are stillincredibly deeply located when compared to the conjunctival vessels.These muscles 1168, 1169, 1170, 1171 which are in proximity to theconjunctiva can be used as a electromechanical source of energy for theImplantable ICLs.

FIGS. 69A and 69B show the surprising large conjunctival area fordiagnostics in accordance with the present invention. There are twolarge pockets, one superior 1180 and one inferiorly 1182. These eye lidspockets are lined by the vascularized conjunctiva. The pocket formed bythe upper eye lid measures in height about 10 to 12 mm in a half moonshape by 40 mm in length. The lower eye lid pocket measures about 8 to10 mm in height by 40 mm in length and can easily accommodate an ICL1184 according to the principles of the invention. FIG. 69A also showsthe different locations for the conjunctiva, the bulbar conjunctiva 1186lining the eye ball and the palpebral conjunctiva 1188 lining the eyelid internally covering the whole eye lid pocket.

FIG. 69B shows a cross-sectional side view of the eye lid pocketsinferiorly with an ICL 1190. Superiorly the figure shows the lid pocketin a resting state and a distensible state. The eye lid pocket is quitedistensible and can accommodate a substantially thick device.

FIG. 69C shows the vascular supply of the lids and conjunctiva includingfacial vessel 1194, supraorbital vessel 1196, lacrimal vessel 1198,frontal vessel 1200 and transverse facial vessel 1202. The eye is theorgan with highest amount of blood flow per gram of tissue in the wholehuman body. This high vascularization and blood supply provides thefluid flow and volume for measurement in accordance with the currentinvention. Dashed lines in FIG. 69C mark the eye lid pockets, superiorly1204 and inferiorly 1206.

FIG. 69D shows a photograph of the palpebral conjunctiva 1207 a andbulbar conjunctiva 1207 b with its blood vessels 1208 a, 1208 b. Theconjunctival vessels 1208 a, 1208 b consists of a multilayered vascularnetwork pattern easily visible through the thin conjunctival epithelium.The structural vascular organization of the conjunctiva creates afavorable arrangement for measurement according to the principles of theinvention since the capillaries lie more superficially, the veins moredeeply and the arteries in between. However considering that theconjunctiva is extremely thin, the distance from the surface isvirtually the same for all three types of vessels. The photograph isbeing used with the sole purpose to clearly illustrate the conjunctivalblood vessels. The bottom part of the figure shows the palpebralconjunctiva 1207 a with the eye lid everted to show the blood vessels1208 a which lines the eye lids internally. Above that one can see thebulbar conjunctiva 1207 b and its blood vessels 1208 b covering the eyeball (white part of the eye). On top of the figure, the cornea 1209 a ispartially shown and the limbal area 1209 b, which is the transitionbetween cornea and conjunctiva.

FIG. 70A shows an exemplary embodiment of a non-invasive glucosedetection system with the ICL 1220 in accordance with the principles ofthe invention with the ICL being powered by electromagnetic inductioncoupling means 1210 produced at a remotely placed source such as awrist-band 1212 or alternatively the frame of eye glasses.Electromagnetic energy from the wrist-device is transferred to anultracapacitor 1214 in the ICL 1220 which acts as the power source forthe ICL working on a power-on-demand fashion supplying power in turn tothe sensor 1216 which is then activated.

Subsequent to that, the glucose level is measured by the sensor 1216 asan electrical current proportional to the concentration of glucose inthe eye fluid which is then converted into an audiofrequency signal bythe integrated circuit radio frequency transceiver 1218. Theaudiofrequency signal 1222 is then transmitted to the wrist-bandreceiver 1212, with said audiofrequency signal 1222 being demodulatedand converted to an electrical signal corresponding to the glucoseconcentration which is displayed in the LED display 1224 according tothe principles of the invention. Subsequent to that, with the use of amicroprocessor controlled feed-back arrangement, the wrist-band device1212 transdermally 1226 delivers substances from reservoir 1228 by meanssuch as iontophoresis, sonophoresis, electrocompression,electroporation, chemical or physical permeation enhancers, hydrostaticpressure or passively with the amount of substance delivered doneaccording to the levels measured and transmitted by the ICL. Thewrist-band device 1212 besides displaying the glucose level acts as areservoir 1228 for a variety of substances.

FIG. 70B shows a summary of the system which includes the natural motionof looking at a wrist-watch 1229 by eye 1231 to check time 1230 whichautomatically activate the ICL 1233 to transmit the signal 1232 anddeliver the substance into the user=s skin 1234.

FIG. 70C shows an exemplary embodiment in which the same steps are takenas described above with the ICL 1239 located in the lower eye lid pocket1236 which is remotely activated by signal 1238, but now the delivery ofsubstances 1244 is done by an ICL 1240 located in the upper eyelidpocket 1242 that acts as a drug reservoir using the same principles asiontophoresis, sonophoresis, electroporation, electrocompression,chemical or other physical enhancers, hydrostatic pressure or passivelyaccording to the levels measured. The characteristics of the conjunctivaallows a Therapeutic ICL to deliver chemical compounds in a variety ofways both conventionally (invasive or simple absorption as with eyedrops) and non-conventionally as described above.

The fact that the conjunctiva does not have a high electricalresistance, since the conjunctiva does not have stratum corneum and highlipid content, makes the conjunctiva an ideal place for using ICL drugdelivery system associated with stimulus by electrical energy.Therapeutic ICLs can also contain sensors that detect the chemicalsignature of diseases and cancers before they turn into life-threateningconditions. Once the disease is identified, therapeutic solutions arereleased, for instance smart bombs, which kill, for instance cancercells, according to the chemical signature of the cancer cell. TheTherapeutic ICLs can deliver a plurality of drugs contained inmicrochips according to information provided by the sensor. Although theTherapeutic ICL system is preferably used in conjunction with chemicaldetection, it is understood that the Therapeutic ICLs can work as a drugdelivery system as an isolated unit in accordance with the principlesdescribed in the current invention. Therapeutic is referred to herein asa means to deliver substances into the body using an ICL placed in theeye.

FIG. 71 shows the flow diagram with steps of the function using thesystem in FIG. 70. The ICL is remotely powered in order to decrease costand the amount of hardware in the body of the ICL, creating extra spacefor a multisensor system. Furthermore, the power-on-demand system allowthe user to have control on how many times to check the glucose levelaccording to the prescription by their doctor. Sometimes patients needto check only at certain times of the day, this design allows a morecost-effective device for each patient individually. Using an activesystem, the ICL can be set to periodically and automatically check theglucose level. Patients who need continuous monitoring can have a powersource in the lens or alternatively with a continuous electromagneticcoupling derived from a source placed in the frame of eye glasses. Inaccordance with the current description at step 1250, the user activatesthe wrist-watch. Then at step 1252 the user looks at his wrist-watch inthe conventional manner to check time. At step 1254 the ICL sensor ispowered and at step 1256 the sensor is activated with the analytemeasured at step 1258. At Step 1260 the integrated circuit radiofrequency transceiver converts the electrical signal into an audiosignal. At step 1262 the wrist-watch converts the audio signal into anumerical value. Step 1264 checks the numerical value acquired againstnormal numerical value stored for the user. At step 1266 substance isdelivered to the user in order to achieve normal range for the user.

FIG. 72A shows an exemplary embodiment of a microfluidic ICL 2000comprised of a network of microchannels 1270 in communication with eachother and with reaction chambers 1272 and reservoirs 1274. The systemincludes a combination of a microfluidic analysis system and abiosensing system, power source 1276, electrical controller 1278,microprocessor 1280 with an integrated circuit radio frequencytransceiver 1282 and a remotely placed receiver system 1284. The centralelectrical controller 1278 applies electrical energy to any of thechannels 1286, reservoirs 1274 or/and reaction chambers 1272 in whichevaluation occurs according to the application used. With theappropriate electrical stimulus, mechanical stimulus, diffusion or/andcapillary action or a combination thereof, either naturally by the eyeor artificially created, eye fluid and/or cells moves through aselectively permeable membrane into the primary chamber 1288 which is inapposition with the conjunctival surface.

FIG. 72A also shows wires 1290 and electrodes 1292 which are placed incontact with the fluid channel 1270, chambers 1272, 1273 and/orreservoirs 1274 for applying electrical energy in order to move anddirect the transport of fluid in the network of microchannels 1270 withthe consequent electrokinetic motion of the substances within the ICLmicrochannel network 2000 according to the application used. The ICLmicrofluidic system includes a control and monitoring arrangement forcontrolling the performance of the processes carried out within thedevice such as controlling the flow and direction of fluid, controllinginternal fluid transport and direction, and monitoring outcome of theprocesses done and signal detection. The dimensions of the microchannelsare in the microscale range on average from 1 μm to 300 μm with themembrane surface in the primary chamber with dimensions around 300 μm indiameter and with the microchannels and chambers containing positiveand/or negative surface charges and/or electrodes in its surface such asfor example thin film electrodes. Electrokinetics are preferably used tomove fluids in the network of microchannels and chambers creating auniform flow velocity across the entire channel diameter.

Although a pressure-driven system can be used, in this pressure drivenin the system the friction that occurs when the fluid encounters thewalls of the channels results in laminar or parabolic flow profiles. Agood example of such flow profile is present in the blood vessels whichis a laminar flow in a pressure-driven system powered by the pumpingfunction of the heart. These pressure-driven system generatesnon-uniform flow velocities with the highest velocity in the middle ofthe microchannel or blood vessel and close to zero as it moves towardsthe walls.

As previously described, the microfabrication techniques and materialsused in the semiconductor industry can be used in the manufacturing ofthe ICL microfluidic system allowing etching of microscopic laboratoriesonto the surface of chips made of silicon, glass or plastic with thecreation of microchannels which allow uniform flow. The power supply1276 in combination with the electrical controller 1278 according to theapplication needed delivers electrical energy to the various electrodes1292 in the channel network which are in electrical contact with thefluid and/or cells acquired from the eye. In the exemplary embodiment acouple of reaction chambers 1272, 1273 are depicted.

Reaction chamber 1272 has a temperature sensor 2002 and reaction chamber1273 has a pressure sensor 2004, while a pH sensor 2006 is placed in thewall of the channel in order to detect pH changes as the fluid flowsthrough the microchannel 1270. The signals from the sensors are coupledto the controller 1278 and microprocessor 1280 by wires 2008 (partiallyshown and extending from electrodes 2202, 2204 and 2006) and radiofrequency transceiver 1282 for further processing and transmission ofsignal to a remote receiver 1284. The outer ICL structure 2010 works asan insulating coating and shields the eye environment from the chemicaland physical processing occurring in the ICL microfluidic system 2000.

FIG. 72B illustrates the microfluidic ICL placed on the surface of theeye laying against the conjunctival blood vessels 2013 with mountedmicrofluidic system 2012, controller 2014, power source 2016 andtransmitter 2020 which are connected by fine wires 2018 (showing onlypartially extending from power source 2016 to the integrated circuitprocessor transmitter 2020 and controller 2014 via wires 2019, alsopartially shown). The signals acquired from the analysis of eye fluidand cells is then transmitted to a remote receiver 2022. The sensingunit 2026 is placed in complete apposition with the conjunctival surfaceand its blood vessels 2024. Although in the schematic illustration thereis shown a small space between the surface of the ICL and theconjunctival surface, in its natural state the surface of the ICL is incomplete apposition with the surface of the conjunctiva due to thenatural tension and force of the eye lid (large arrows 2011). Thusallowing the ICL to easily acquire cells (surface of the eye is composedof loosely arranged living tissue) and/or fluid from the surface of theeye with the cells and/or fluid moving into the ICL microfluidic systemas the small arrows indicate.

FIG. 73A illustrates an exemplary embodiment of the microfluidic ICL2030 with a network of interconnected microchannels 2032 and reservoirswith reagents with each microcavity preferably containing a separatetesting substance with the microfluidic ICL 2030 in apposition with theconjunctiva 2052. This exemplary embodiment also includes disposalreservoir 2034, detection system and ports for electrodes (not shown) aspreviously described.

The ICL electrical system applies selectable energy levelssimultaneously or individually to any of the microcavities or channelsby electrodes positioned in connection with each of the reservoirs. Thesubstances present in the reservoirs are transported through the channelsystem with the precise delivery of the appropriate amount of substanceto a certain area or reaction chamber in order to carry out theapplication.

In accordance with the invention, the fluid and/or cells from the eyeare introduced at 2036 into the ICL microfluidic system with materialsbeing transported using electrokinetic forces through the channels 2032of the ICL microfluidic system 2030. After the eye fluid is introducedin the ICL microchannel network 2032, the fluid is manipulated to createan interaction between at least two elements creating a detectablesignal. In accordance with the invention, if a continuous steady flow ofeye fluid occurs in the microchannels but no detectable element ispresent, then no detectable optical signal is generated by opticaldetection system 2038, thus no signal is acquired and transmitted. Iffor instance the immunointeraction creates a change in the opticalproperty of the reaction medium, then the detectable signal indicatesthe presence of the substance being evaluated and an optical signal isgenerated by optical detection system 2038. Thus a detectable opticalsignal is created and transmitted. This embodiment includes a detectionzone 2040 for optical detection of for example chemiluminescent materialor the amount of light absorbed using a variety of optical detectionsystems and laser systems. Exemplary optical techniques includeimmunosensors based on optical detection of a particularimmunointeraction including optical detection of a product of anenzymatic reaction formed as a result of a transformation catalyzed byan enzyme label as well as direct optical detection of theimmunointeraction and optical detection of a fluorescent labeledimmunocomplex.

An exemplary embodiment in accordance with the invention shows the eyefluid 2036 flowing through the microchannel network 2032 from theprimary chamber 2042 with a certain heart marker (antigen) present inthe eye fluid. Measurement of the heart markers such as for examplePAI-1 (plasminogen activator inhibitor) indicates the risk ofcardiovascular disease and risk of a life-threatening heart attack.Other markers such as troponin T can help identify silent heart damage.Many patients sustain heart attacks, but because of the lack ofsymptoms, the heart damage goes undetected.

When a second heart attack then occurs with or without symptoms there isalready too much damage to the heart leading then to the demise of thepatient, sometimes described as sudden cardiac death. However, inreality the deterioration of the heart was not sudden, but simplyfurther damage that occurred associated with an undetected initial heartdamage. If silent heart damage was identified, the patient could havebeen treated on a timely manner. If a marker that shows risk for heartdamage before the damage occurs is identified, then the patient can betimely treated and could have normal life. However, a patient at risk ofa heart attack in order to identify a marker for damage has to havedaily monitoring which is now possible with the present invention.

In accordance with the invention, the eye fluid is transported to themain channel 2044 and then periodically a certain amount of antibody tothe PAI-1 (antibody) flows from reservoir 2046 into the main channel2044 with the consequent mixing of antigen and antibody and theformation of an antigen-antibody complex considering that the heartmarker PAI-1 (antigen) is present in the eye fluid. The formation of theantigen-antibody complex in the surface of the optical transducer 2048creates a detectable signal indicating the presence of the marker.

A low-cost exemplary embodiment comprises of simultaneous activation ofa light source 2050 and flow of antibody to the main channel 2044. Thislight source 2050 is coupled to a photodetector 2038 and lens. If themarker is present, then the creation of the antigen-antibody complexleads to a change in the amount of light reaching the photodetector 2038indicating the presence of the marker. The surface of the optical system2048 can also be coated with antibody against the antigen-antibodycomplex which would create a coating of the optical system 2048 creatinga shield with the consequent significant decrease of light reaching thephotodetector 2038 coming form the light source 2050. The signal is thentransmitted to the user informing them that the heart marker wasdetected since there was a signal coming from optical detector 2038 andin view of that, the optical system surface is covered with a specificantibody. Then, the signal generated refers to the presence of theantigen. Although only one detection system is described, a multiplesystem can be achieved with detection of multiple substances and/ormarkers simultaneously. Any other, fluid or material can thensubsequently be transported to the disposal reservoir 2034. Althoughonly one exemplary optical detection was described in more detail it isunderstood that any optical detection system can be used for carryingout the present invention including other optical immunosensing systems.

FIG. 73B shows an ICL microfluidic system 2060 in apposition with theconjunctiva 2052 with various capabilities in accordance withelectrokinetic principles, microfluidics and other principles of theinvention. The fluid from the eye 2066 is moved into the primarymicrochannel 2062 of the ICL microchannel network 2064 by capillaryaction associated with the mechanical displacement 2070 of fluid by theprotruding element 2068 with further pushing of fluid and/or cells intothe ICL microchannel 2062. The design of this ICL creates an enhancementof flow that may be needed according to certain applications.

This design with protrusion element 2068 creates a strong apposition ofthe ICL 2060 against the conjunctival surface 2052. An interestinganalogy relates to a person laying on a bed of nails in which the nailsdo not penetrate the skin because the force is evenly distributed alongthe body surface. If only one nail is displaced upwards the nail willpenetrate the skin. The same physical principle of equal distribution offorces apply to this design.

The conjunctiva 2052 is a moldable tissue and thin, and the evendistribution of pressure by a smooth ICL surface leads to a certainpermeation rate. However if a protrusion 2068 on the surface of the ICLis created there is an increase in the rate of permeation and capillaryaction due to the surrounding pressure and uneven distribution ofpressure forcing more fluid and cells into the ICL microchannel 2062.This ultra rapid passive flow may be important when multiple substances,fluid and cells are analyzed in a continuous manner such as multiplegene analysis. Most important is that the conjunctival area proves againto be the ideal place for diagnostics with the ICL system since theconjunctiva, contrary to other parts of the body, does not have pressuresensing nerve fibers and thus a patient does not feel the protrusion2068 present in the surface of the ICL, although the protrusion is stillvery small.

In accordance with the invention, the fluid moves into microcavity 2072which consists of a glucose oxidase amperometric biosensor. The glucoselevel present in the eye fluid is then quantified as previouslydescribed and the glucose level of the sample eye fluid 2066 being thenidentified and transmitted to a remote receiver via micro lead 2074(partially shown). Processing then can activate electrical energy tomove the eye fluid 2066 to microcavity 2076 which contains an antibodyfor a certain drug. A reaction antigen-antibody then occurs in responsethereto if the drug being evaluated is present in the eye fluidcollected forming an antigen-antibody complex. The eye fluid with theantigen-antibody complex actively or passively moves to microcavity 2078which contains a catalytic antibody to the antigen-antibody complex. Thecatalytic antibody is immobilized in a membrane with associated pHsensitive electrodes 2080. The antigen-antibody complex when interactingwith the catalytic antibody present in the microcavity promotes theformation of acetic acid with a consequent change in pH and formation ofa current proportional to the concentration of antigens—in thisillustration, a certain drug allowing thus therapeutic drug monitoring.

The exemplary embodiment also includes microcavity 2082 which containsimmobilized electrocatalytic enzyme and associated electrode 2084, whichin the presence of a substrate, for instance a certain hormone, producean electrocatalytic reaction resulting in a current proportional to theamount of the substrate. Fluid is then moved to microcavity 2086 inwhich a neutralization of chemicals can be achieved before leaving thesystem through cavity 2088 into the surface of the conjunctiva 2090 withthe neutralization for instance including neutralization of pH regardingthe potential presence of chemicals produced such as remaining aceticacid from cavity 2078.

The ICL system then can repeat the same process, for example, every hourfor continuous monitoring, including during sleeping. Although theamount of acid formed and reagents is minute and the tear film washesmuch more noxious elements, a variety of safety systems can be createdsuch as selectively permeable membranes, valves, neutralizationcavities, and the like. A variety of elements can be detected with thetests performed by the ICL such as microorganisms, viruses, chemicals,markers, hormones, therapeutic drugs, drugs of abuse, detection ofpregnancy complications such as preterm labor (such as detecting FetalFibronectin), and the like.

FIG. 73C shows a schematic view of the microfluidic ICL with the networkof microchannels 2092 located in the body of the ICL microfluidicsubstrate 2094 and the primary chamber 2096 comprising a protrudingelement configuration. It is noted that the microfluidic system consistsof an ultrathin substrate plate as with a silicon chip but with a largerdimension in length which fits ideally with the anatomy of the eye lidpockets.

FIG. 74A shows an ICL 2100 for glucose monitoring placed in the lowereyelid pocket 2102 in apposition to the conjunctival surface and bloodvessels 2104 present in the surface of the eye. The exemplary ICL shownin FIG. 74B on an enlarged scale includes in more detail the sensor 2106for detection of glucose located in the main body of the ICL 2100 withits associated power source 2108 and-transmitter system 2110. The sensorsurface 2106 extends beyond the surface of the remaining ICL surface inorder to increase flow rate of fluid to the sensor and associatedmembrane.

FIGS. 74C and 74E show the eye lid pumping action in more detail movingfluid toward the sensor 2106 and creating complete apposition of the ICL2100 with the conjunctiva 2112. The presence of the ICL 2100 in the eyelid pocket 2114 in FIG. 74E stimulates the increase in tension of theeye lid creating an instantaneous natural pumping action due to thepresence of the ICL 2100 in the eye lid pocket 2114.

FIG. 74D shows the same ICL 2100 as in FIG. 74B but with an associatedring of silicone 2120 surrounding the protruding membrane area to betterisolate the area from contaminants and surrounding eye fluid.

The ICL shown in FIG. 75A includes the exposed membrane 2122 surroundedby a silicone ring 2120. Although silicone is described, a variety ofother adherent polymers and substances can be used to better isolate themembrane surface from the surrounding eye environment. FIG. 75A shows aplanar view and FIG. 75B shows a side view. FIG. 75C shows an exemplaryembodiment with the whole sensor and membrane being encased by the ICL2124. In this case polymers which are permeable to glucose can be usedand the whole sensor and hardware (transmitter and power supply) isencased by a polymer. The membrane sensor area 2122 encased in the lensbody 2126 can be completely isolated from the rest of the hardware andlens matrix in the body of the lens 2126. In this embodiment a channel2128 within the body of the lens 2126 which can have an irregularsurface 2129 to increase flow, is created thus isolating and directingthe eye fluid for precise quantification of the amount of glucoseentering a known surface of the lens 2130 and reaching the surface ofthe membrane sensor 2122 as shown in FIG. 75D. A silicone ring 2120 isplaced on the outer part of the channel 2128 to isolate the channel 2128from the surrounding environment of the eye. By completely encasing thesensor system, the surface of the ICL covering the membrane can be madewith various shapes and surface irregularities in order to increaseflow, create suction effect, and the like.

FIG. 76 shows an ICL with optical properties in the center 2140 as inconventional contact lenses, with sensing devices and other hardwareencased in a ring fashioned around the optical center 2140. This ICLincludes a microfluidic system 2142, a biosensor 2144, power supply withcontroller 2146 and transceiver 2148 connected by various wires 2150.

FIG. 77 shows an exemplary embodiment in which, in contrast to a lenssystem, a manual rod-like system 2160 is used in which the user holds anintelligent rod 2160 which contains the hardware and sensing unitsaccording to the principles of the present invention. The user thenplaces the sensor surface 2162 against the eye, preferably by holdingdown the lower eye lid. The sensor surface 2162 then rests against theconjunctival surface 2164 and the measurement is done. Since with thisembodiment the user looses the pump action, friction, and naturalpumping action of the eye lid, the user can, before placing the sensorsurface against the eye, rub the opposite side of the sensor which inthis case would have an irregular surface, in order to create the flowas naturally produced by the eye lid physiologic action. This embodimentcan be used by a user who only wants one measurement, let-s say forinstance to check-cholesterol levels once a month. The embodiment alsowould be useful for holding an enormous amount of hardware and sensingdevices since the rod 2160 can be made in any dimension needed while thelens has to fit within the eye anatomy. The other advantage of thisother embodiment is that there is no need for wireless transmission asthe handle itself can display the results. One must keep in mind thoughthat this embodiment is not well suited for continuous measurement andalso would demand an action by the user contrary to the lens embodimentwhich measurement takes place while the user performs his/her dailyroutines.

Alternatively, the tip of the rod can be coated with antigen. The tip isthen rubbed or placed against the conjunctiva and/or surface of the eye.If antibodies to the antigen are present a detectable signal isproduced, with for instance a variety of electrical signals aspreviously described. The tip of the rod can contain a variety ofantigens and when any one of those is identified by the correspondingantibody a specific signal related to the antigen is produced.Alternatively, the tip can have antibodies and detect the presence ofantigens. Naturally the simpler systems described above can be used inany embodiment such as a rod, contact lens, and the like.

FIG. 78A shows a two piece ICL in both conjunctival pockets, superiorly2170 and inferiorly 2172. The ICL placed superiorly includes amicrofluidic ICL 2174 positioned against the conjunctival surface withthe eye fluid 2176 moving from the conjunctiva as shown in more detailin FIG. 78B. The fluid and cells 2176 move into the ICL microchannelnetwork in accordance with the eye lid pumping effect and the otherprinciples of the present invention. This exemplary ICL also includes acouple of reaction chambers 2178 and microvalves and membranes 2180within the microchannels.

FIG. 78C shows in more detail the ICL 2186 placed in the lower eye lidpocket 2172. This exemplary ICL includes a reservoir 2182 which isfilled over time with eye fluid and/or cells 2176 for further processingafter removal from the eye. This embodiment also includes a biosensor2184. Thus said ICL 2186 has a dual function of immediate analysis offluid as well as storage of eye fluid with part of the-fluid beinganalyzed in the ICL body with the part of fluid permeating a selectivepermeable membrane 2186 in the surface of the biosensor 2184.

The ICL in FIG. 79A includes an electroporation system and other meansto transfer a variety of substances, molecules and ions across tissuewith increase in permeability of tissues associated with an electricalstimulus for transport of the substances, molecules and ions. Electrodesin contact with the conjunctival surface 2192 minimally invasivelyremove fluid and/or penetrate surface 2192 with minimal sensation. Avariety of fine wires (not shown) can also be used and penetrate thesurface 2192 with minimal sensation. Those systems can be more ideallyused with ICLs and in contact with the conjunctiva 2192 than with skindue to the more appropriate anatomy of the conjunctiva 2192 asdescribed, compared to the skin since the conjunctiva 2192 is a verythin layer of tissue with abundant plasma underneath. The ICL in FIG.79B include a physical transport enhancement system 2194 such asapplication of electrical energy and/or creation of an electrical fieldto increase flow of fluid and/or substances into the ICL sensingsystems. The ICL in FIG. 79C includes a chemical transport enhancementsystem 2196 such as an increase of permeation of a variety ofsubstances, such as for example increased flow of glucose with the useof alkali salts.

Although not depicted, a variety of combinations of ICLs can beaccomplished such as total, partial or no encasement of the sensorsurface and with or without isolation rings, with or without transportenhancers, with or without protruding areas, with or without surfacechanges, and the like.

FIG. 80 shows a microfluidic chip ICL 2200 which includes a couple ofsilicon chips 2202, 2204 in a 5-by-5 array electrode arrangement, areaction chamber 2206 and a disposal chamber 2208. Cells and fluid 2212from the surface of the eye are pumped into the main microchannel 2210with the first chip 2202 electrically separating cells and fluid withsubsequent analysis of substances according to the principles of theinvention. The cellular elements are then moved into the reactionchamber 2206 in which electric current is applied and break the cellwalls with extrusion of its contents. Specific enzymes for organellespresent in the reaction chamber 2206 degrade the proteins and organellespresent but without affecting nucleic acids such as DNA and RNA. Thereleased DNA and RNA can then be further analyzed in the second chip2204 or in a microchannel fluidic system as previously described. Avariety of oligonucleotide probes can be attached to reaction chambers2206 or microcavities in chips 2204 or in chambers in microfluidicsnetwork in order to capture specific nucleic acid with the creation of adetectable signal such as an electrical signal in which an electrode iscoupled with said probe. The ICL technology, by providing a continuousor quasi-continuous evaluation, can identify a mutant gene, for instancerelated to cancer or disease, among a large number of normal genes andbe used for screening high risk populations or monitoring high riskpatients undergoing treatment as well as identifying occult allergiesand occult diseases and risk for certain diseases and reactions to drugsallowing preventive measures to be taken before injury or illness occuror timely treating the illness before significant damage occurs.

The Human Genome Project will bring valuable information for patientsbut this information could be underutilized because patients do not wantto be tested with fear of rejection by insurance companies. People withgenetic predisposition to certain disorders could have a difficult timeto find health insurance and/or life insurance coverage.

With the prior practices for genetic testing done in laboratories,patients could be vulnerable to disclosure of their genetic profile.Unfortunately, then life-saving genetic information that allows earlydetection and early treatment is not going to be fully used to thebenefit of patients and society in general.

The ICL system by providing the PIL (Personal Invisible Laboratory)allows the user to do self-testing and identify genetic abnormalitiesthat can cause diseases in a complete private manner. The genetic ICLPIL can, in a bloodless and painless fashion, identify the geneticpredisposition to diseases, and sometimes just a change in diet cansignificantly decrease the development of these diseases.

With the current invention the patient can privately, individually andconfidentially identify any disease the patient is at risk of, and thentake the necessary measures for treatment. For example, if a patient hasgenes which are predisposed to glaucoma, a blinding but treatabledisease, then the patient can check his/her eye pressure more often andvisit eye doctors on a more frequent basis.

Some cancers are virtually 100% fatal and unfortunately not becausethere is no cure or treatment available but because the cancer was nottimely identified. A devastating example concerns a cancer in thegenitals or cancer of the ovary. This cancer kills virtually 100% of thewomen who are diagnosed with this cancer. It is the highest fatalityrate for all cancers in women and not because there is no cure ortreatment, but because there are no symptoms or signs that would alertthose women to seek medical attention, and even sometimes routineexamination by the doctor does not identify the occult malignancies.

If a woman knows she has a genetic predisposition for ovarian cancer,being privately and confidentiality identified with the ICL PIL systems,the patient can take the necessary preventive steps, be treated on atimely fashion, and have normal life. A simple small surgery of justremoving the affected tissue can be curative, compared to thecatastrophic many months of surgeries, chemotherapy and other aggressivetherapies, previously used as a course of treatment still only to delaythe inevitable demise.

There are many medical situations affecting both men and women, adultsand children alike concerning similar situations and diseases as thedescribed ovarian cancer. In general, the most devastating and fataldisorders are the silent ones, which sometimes are very easy to treat.The current invention thus allows full and secure use of informationprovided by the Human Genome Project in which only the user alone, andnobody else will know about a particular genetic predisposition. Theuser acquires the ICL of interest and places it in the eye and receivesthe signal using a personal device receiver.

FIG. 81 shows a complete integrated ICL 2220 with a three-layerconfiguration. The top layer 2222 which rests against the conjunctivacontains microchannels, reservoirs, and reaction chambers where thechemical reactions take place. The middle layer 2224 has the electricalconnections and controller that controls the voltage in the reservoirsand microchannels and the bottom layer 2226 contains the integratedcircuit and transmission system.

FIGS. 82A through 82D shows an exemplary embodiment of an implantableICL. As mentioned the conjunctiva is an ideal place since it is easilyaccessible and the implantation can be accomplished easily using onlyeye drops to anesthetize the eye. There is no need to inject anestheticfor this procedure which is a great advantage compared to other areas ofthe body. It is interesting to note that amazingly the conjunctiva healswithout scarring which makes the area an even more ideal location forplacement of implantable ICLs.

FIG. 82A shows exemplary areas for placement of the ICL under theconjunctiva 2232 (area 1), 2234 (area 2) and/or anchored to the surfaceof the eye (area 3) 2236. Implantable ICL 2238 (area 4) uses abiological source such as muscular contraction of the eye muscles togenerate energy. The eye muscles are very active metabolic and cancontinuously generate energy by electromechanical means. In thisembodiment the eye lid muscles or extra-ocular muscles 2240 which lieunderneath the conjunctiva is connected to a power transducer 2242housed in the ICL 2238 which converts the muscular work into electricalenergy which can be subsequently stored in a standard energy storagemedium.

FIG. 82B shows in more detail the steps taken for surgical implantation.After one drop of anesthetic is placed on the eye, a small incision 2244(exaggerated in size for the purpose of better illustration) is made inthe conjunctiva. As shown in FIG. 82C, one simply slides the ICL 2230under the conjunctiva which by gravity and anatomy of the eye sits inthe eye lid pocket, preferably without any fixation stitches. FIG. 82Dshows insertion of the ICL 2246 by injecting the ICL 2246 with a syringeand needle 2248 under the conjunctiva 2250. The conjunctiva will healwithout scaring.

The location identified in the invention as a source for diagnostics andblood analysis can be used less desirably in a variety of ways besidesthe ones described. Alternatively a cannula can be placed under or inthe conjunctiva and plasma aspirated and analyzed in the conventionalmanner. Furthermore a suction cup device can be placed on the surface ofthe conjunctiva and by aspiration acquire the elements to be measured.These elements can be transferred to conventional equipment or thesuction cup has a cannule directly connected to conventional analyzingmachinery.

The ICL 2260 in FIG. 83 includes a temperature sensor 2262 coupled to abioelectronic chip 2264 for identifying microorganisms, a power source2266, a transmitter 2268 and a receiving unit 2270. When bacteria reachthe blood stream there is usually an associated temperature spike. Atthat point there is maximum flow of bacteria in the blood. Thetemperature spike detected by temperature sensor 2262 activatesbioelectronic chip 2264 which then starts to analyze the eye fluidand/or cells for the presence of bacteria, with for example probes forE. coli and other gram negatives and gram positives organisms associatedwith common infections. The information on the organisms identified isthen transmitted to a receiver allowing immediate life-saving therapy tobe instituted on a timely fashion.

Previously, nurses had to check the patient=s temperature on a veryfrequent basis in order to detect temperature changes. Naturally this isa labor intensive and costly procedure. Then if the nurse identifies thetemperature change, blood is removed from the patient, usually threetimes in a row which is a quite painful procedure. Then the blood has tobe taken for analysis, including cultures to detect the organism and maytake weeks for the results to come back. Sometimes because of a lack oftimely identification of the infectious agents the patients dies eventhough curative treatment was available. The ICL thus can providelife-saving information for the patients. Naturally the ICL temperaturecan be used alone as for instance monitoring infants during the nightwith an alarm going off to alert the parents that the child has a fever.

FIG. 84 shows a dual system ICL used in both eyes primarily for use inthe battlefield with the ICL 2280 for tracking placed in the right eyeand ICL 2282 for chemical sensing placed in the left eye with the ICL2280 and/or 2282 placed externally on the eye or surgically temporarilyimplanted in the conjunctiva which allows easy surgical insertion andremoval of the ICLs as described in FIGS. 82A through 82D. Thetracking-chemical ICL system also includes a receiver 2290. Radio pulses2292 based on GPS technology are emitted from satellites 2284, 2286,2288 in orbit as spheres of position with alternative decoding by groundunits (not shown) which gives the position of the transceiver ICL 2280placed in the right eye. ICL 2280 can be periodically automaticallyactivated for providing position. If a biological or chemical weapon isdetected by chemical sensing ICL 2282, the receiver 2290 displays theinformation (not shown) and activates the tracking ICL 2280 toimmediately locate the troops exposed. Alternatively, as soon asreceiver 2290 receives a signal concerning chemical weapons, the userscan then manually activate the tracking ICL 2280 to provide their exactposition.

It is understood that as miniaturization of systems progress a varietyof new separation and analysis technologies will be created and can beused in the present invention as well as a combination of otherseparation systems such as nanotechnology, molecular chromatography,nanoelectrophoresis, capillary electrochromatography, and the like. Itis also understood that a variety of chips, nanoscale sensing devices,bioelectronic chips, microfluidic devices, and other technological areaswill advance rapidly in the coming years and such advances can be usedin the ICL system in accordance with the principles of the invention.

The ICL PIL systems allow any assay to be performed and any substance,analyte or molecule, biological, chemical or pharmacological andphysical parameters to be evaluated allowing preventive and timelytesting using low-cost systems while eliminating human operatorsinvolved in hazardous activities including the accidental transmissionof fatal diseases such as AIDS, hepatitis, other virus and prions, andthe like.

Contrary to the prior art that has used non-physiologic and non-naturalmeans to perform diagnostics and blood analysis with means such astearing and cutting the skin with blades and needles, shocking,destroying tissue electrically or with lasers, placing devices in themouth that can be swallowed and have no means for natural apposition,and so forth, the present invention uses placement of an ICL in andisturbed fashion in order to acquire the signal, with the signal beingphysiologically and naturally acquired as the analytes are naturally andfreely delivered by the body.

If one thinks about the conjunctival area and sensors according to theprinciples of the invention, and consider that the area not only hassuperficial blood vessels, but also has fenestrated blood vessels withplasma pouring from the lumen through the holes in the vessel wall, onewould appreciate the ideal situation of the present invention. However,further, the blood vessels are easily accessible, no keratin is presentand also living tissue is present on the surface allowing complete fluidand cell analysis. Moreover a very thin and permeable epitheliumassociated with a very homogeneous thickness throughout its wholesurface is available with the direct view of the blood vessels. Also,natural eye lid force acts as a natural pump for fluid.

Furthermore, sensors are placed in natural pockets, and there is notjust one small pocket, but four large pockets with over 16 squarecentimeters of area that can be used as a laboratory. In this pocket asensor can be left completely undisturbed without affecting the functionof the eye and due to high oxygen content in the surface of theconjunctiva the ICL can be left in place for long periods of time, evena month based upon material currently available for long-term use in theeye. In addition, the area is highly vascularized, and the eye has thehighest amount of blood per gram of tissue among all organs in the humanbody. Furthermore, it provides not only chemical parameters, but alsothe ideal location for physical parameters such as measurement oftemperature since it gives core temperature, pressure and evaluation ofthe brain and heart due to the direct connection of the eye with thebrain and the heart vasculature and innervation. In addition, the areais poorly innervated which means that the patient will not feel the ICLdevice that is placed in the pocket, and the lid supports the devicenaturally with an absolutely cosmetically acceptable design in which theICLs are hidden in place while non-invasively providing life-savinginformation.

The ICL PIL offers all of that plus time-savings and effort-savingsallowing users to take care of their health while doing their dailyactivities in a painless fashion and without the user spending money,time and effort to get to a laboratory and without the need tomanipulate blood associated with benefits of decreasing harm byillnesses, preventing life-threatening complications by variousdiseases, timely identifying cancers and other diseases, monitoringglucose, metabolic function, drugs and hormones, calcium, oxygen andother chemicals and gases, and virtually any element present in theblood or tissues, detecting antigen and antibodies, locating troopsexposed to biological warfare, allowing timely detection and treatment,temperature detection with simultaneous detection of microorganisms,creation of artificial organs and drug delivery systems, and providingmeans to allow full and secure use of information by the Human GenomeProject, ultimately improving quality of life and increasinglife-expectancy while dramatically reducing health care costs. The ICLPIL thus accomplishes the rare feat in medical sciences of innovationassociated with dramatic reduction of health care costs.

FIG. 85 shows a schematic block diagram of one preferred reflectancemeasuring apparatus of the present invention. The system includes aradiation source 2300 emitting preferably at least one near-infraredwavelength, but alternatively a plurality of different wavelengths canbe used. The light source emits radiation 2302, preferably between 750and 3000 nm, including a wavelength typical of the absorption spectrumfor the substance of interest. The radiation is then filtered andfocused by the optical interface system 2304 onto fiber optic cable 2306which transmits the radiation to the plasma/conjunctiva interface 2310.The plasma/conjunctiva interface 2310 is comprised of the thinconjunctiva lining 2320 with plasma interface 2330 and a substance ofinterest 2350 underneath said conjunctiva 2320. Optic fiber cable 2306is part of a dual optic fiber cable system preferably with fiber cable2306 and collecting fiber cable 2312 located side-by-side. The diameterof the optic fiber is 300 μm, although a variety of diameters can beused.

The radiation is directed at the plasma interface 2330 and delivered viasensor head 2314 in apposition to conjunctival lining 2320. The plasma2330 is present between the thin conjunctival lining 2320 and the sclera2316, a white and water free structure which is the external layer ofthe eyeball. In addition, it is understood that there are areas in theeye which the plasma is interposed between the conjunctiva and ligamentsor other tissues but not the sclera, as it occur in areas in thecul-de-sac (not shown).

The optic fiber 2306 delivers the radiation 2302 provided by the source2300 to the plasma interface 2330. The radiation 2302 directed at theplasma 2330 is partially absorbed and scattered according to theinteraction with the conjunctival lining 2320 and the substance ofinterest 2350 present in the plasma 2330. Conjunctiva 2320 is the onlytissue interposed between radiation 2302 and the substance of interest2350. The conjunctiva 2320 does not absorb near-infrared light andscattering is insignificant as the conjunctiva is an extremely thinmembrane. Part of the radiation 2302 is then absorbed by the substanceof interest 2350 and the resulting radiation emitted from the eyecorresponds to said substance of interest 2350.

The resulting radiation from the eye is reflected back and collected bycollecting optical fibers 2312 via sensor head 2314 and delivered to thedetector 2318. The system includes a spectrum analyzer/detector 2318 fordetecting and analyzing radiation 2302 emitted by the radiation source2300 and which has interacted with the plasma interface, 2330 with saidresulting radiation containing spectral information for the substance ofinterest 2350. The resulting radiation is converted into a signal by thespectrum/analyzer/detector 2318 which can be amplified and converted todigital information by the A/D converter 2322. The information in thenfed into a processor 2324 and memory 2326 for analyzing the spectralinformation contained therein and calculating the concentration of atleast one chemical substance in the eye fluid derived from the resultingspectral information.

The concentration of the substance of interest 2350 is accomplished bydetecting the magnitude of light attenuation collected which is causedby the absorption signature of the substance of interest. Models,calibration procedures, and mathematical/statistical analysis such asmultivariate analysis and PLS can be used to determine the concentrationof the substance of interest 2350 from the measured absorption spectrum.

Data analysis by empirical or physical methods previously mentioned canbe used for analysis of the resulting spectra associated with signalprocessing and which are performed by the processor 2324 includingFourier Transformation, digital filtering, and the like. Algorithm orother analyses are employed to compensate for the background response,noise, source of errors, and variability. Since the spectral informationaccording to the principles of the invention has very few interferingfactors, statistical extraction of the spectra of interest isfacilitated allowing accurate determination of the concentration of thesubstance of interest 2350.

Processor 2324 can contain or be connected to a memory unit 2326 whichcan store data related to calibration, patient's measurement data,reference data, suitable algorithms, and the like. Display part 2328 isadapted to output results of the concentration of the substance ofinterest by the processor. The processor 2324 can also be connected toan audio transmitter 2334, such as a speaker, which can audiblycommunicate abnormal levels, and to a device 2332 for delivery ofmedications according to the concentration of the substance of interest2350.

Since the present invention reduces or eliminates the interferingelements and background interference such as fat, melanin, skin texture,and the like as previously described, the value indicative of theresulting spectra and data analysis accurately and precisely determinethe concentration of the substance of interest 2350.

A variety of radiation sources 2300 can be used in the present inventionincluding LEDs with or without a spectral filter, a variety of lasersincluding diode lasers, halogen lights and white light sources havingmaximum output power in the near infrared region with or without afilter, and the like. The radiation sources 2300 have preferably enoughpower and wavelengths required for the measurements and a high spectralcorrelation with the substance of interest 2350. The range ofwavelengths chosen preferably corresponds to a known range and includesthe band of absorption for the substance of interest 2350.

Light source 2300 can provide the bandwidth of interest with said light2302 being directed at the substance of interest 2350. A variety offilters can be used to selectively pass one or more wavelengths whichhighly correlate with the substance of interest 2350. The lightradiation 2302 can be directly emitted from a light source 2300 anddirectly collected by a photodetector 2318, or the light radiation 2302can be delivered and collected using optic fiber cables. An interfacelens system can be used to convert the rays to spatial parallel rays,such as from an incident divergent beam to a spatially parallel beam.

When a laser light or a continuous wavelength source is employed anoptical interface may not be necessary as one single optical path isderived from the source 2300. The output of a white light source, somelasers, and the like can be coupled directly into the receiving end ofoptical fibers which can be used as a light pipe. Due to the samplecharacteristics of the conjunctiva/plasma interface 2310 as previouslydescribed, the system can use a variety of diodes and detectors beyond2500 nm allowing more spectrum regions to be used which in turnfacilitate the accurate measurement of the substance of interest 2350.

Wavelength selection means can include bandpass filters, interferencefilters, a grating monochromator, a prism monochromator, acousto-optictunable filter, or any wavelength dispersing device. Although dualoptical fibers were used in the illustration, it is understood thatdirect light sources and direct collection detectors can be used as wellas a single fiber optic bundle that transmits radiation to theconjunctiva 2320 and collects resulting radiation from said conjunctiva2320. A variety of amplifiers, pre-amplifiers, and filters and the likecan be used for reducing noise, amplifying signals, filtering,smoothing, and the like. Although an amplifier can be used as described,it is understood that amplification is secondary for the operation.

Now referring to FIG. 86, the apparatus includes a probe 2336 with asensor head 2314 provided on its end with radiation source transmissionfiber 2338 and radiation receiving collector fiber 2342 which arepreferably side-by-side. The distance between the radiation transmissionsource 2338 and the radiation receiving collector 2342 is preferablyaround 0.5 mm, but determined such that the light path.2340 is mostlyformed in the plasma interface 2330. Although only one collecting fiber2342 is illustrated, it is understood that a plurality of collectionfibers positioned at different distances from the source fiber 2338 canbe used. Use of optical fibers enable optimization of delivery with thelight 2346 being piped through optical fibers 2338 and delivered to theplasma/conjunctiva interface 2310.

Still with reference to FIG. 86, the end of source fiber 2338 directsradiation at the plasma interface 2330 where there is a high relativeconcentration of the substance of interest 2350. The radiation 2340interacts with the substance of interest 2350 and the resultingradiation 2348 is collected by the collection fibers 2342 for subsequentmeasuring absorbencies at a wavelength selected for the substance ofinterest 2350 and determining the concentration of said substance ofinterest 2350. The sensor head 2314 can include a wall 2344 positionedbetween the light source 2338 and light collector 2342 to shield thecollector 2342 from light 2346.

In a transparent, thin, and homogeneous structure like theconjunctiva/plasma interface 2310, Beer-Lambert's law can be applied todetermine energy absorption.

As an example, glucose can be chosen as a substance of interest measuredin the conjunctiva/plasma interface in accordance with a preferredembodiment of the invention. Near-infrared reflectance measurement ofplasma glucose adjacent to the conjunctiva was done in association withconventional methods normally used in a laboratory to evaluate plasmaglucose. The “overall setup” includes:

-   -   1. A light source generating multiple wavelengths of near        infrared light.    -   2. Fiber optics. Fiber optics transmits the photons from the        light source to the conjunctival site on the patient and from        the conjunctival site to a detector. In general photons follow        an elliptical path through the sample from the source to the        detector. Fiber optic separation is important in determining the        area of interrogation by the incident photons. The shorter the        interoptode distance, the less deep is the penetration of light.        In the probe arrangement (sensor head) for the conjunctiva, the        optic fibers were separated by a distance of 0.5 mm.        Alternatively, a distance of 0.1 mm was used for interrogating        substances present in the superficial structure of the        conjunctiva/plasma interface and thinner interface areas. The        collecting optic fiber collected the resulting radiation. The        resulting radiation contains spectral information for each        plasma constituent and due to its optimal point of detection as        disclosed in the invention there is no significant background        spectral information.    -   3. Selective filters or diffraction grating systems. These        filter systems are used for selecting wavelength of interest as        well as eliminating wavelength which do not have a high        correlation with the substance of interest. A reference filter        can be used and consists of a narrow bandpass filter which pass        wavelengths which have no correlation with the substance of        interest.    -   4. Photon detection circuitry such as a photomultiplier and        integration amplifier including a lead-sulfide photodetector        which convert the resulting radiation into signals        representative of the intensity of those wavelengths.    -   5. An A/D converter to convert the analog signals from the        photon detection circuit to digital information.    -   6. A central processor with appropriate software (algorithms) to        process the information obtained in the resulting radiation and        compare it with the known amount of reference radiation.    -   7. An information display system to report the result.

A known amount of incident light is used to illuminate the conjunctivausing a probe in apposition to the conjunctiva. The amount of lightrecovered after the photons pass through the conjunctiva depend on theamount of light absorption by the substance of interest and the degreeof light scatter and absorption by the tissue. Scattering as well asabsorption by tissue and other interfering constituents areinsignificant in the conjunctiva as previously described.

In more detail, the testing equipment included a 75 W halogen lightsource coupled to an optic fiber (available from Linos Photonics GmbH,Göttingen, Germany). An optical filter adjusted the wavelength toprovide near-infrared radiation in the 1400-2500 nm spectral range. Theradiation was delivered to the conjunctiva surface using a fiber opticprobe arrangement (sensor head) supported by a Haag-Streit Goldmanntonometer piece and associated Haag-Streit slit-lamp 6E (Haag-Streit,Bern, Switzerland).

The sensor head was coupled to the conjunctival surface of the eye.Reflected radiation that interacted with the conjunctiva was collectedby the collecting optic fiber. The optic fiber delivered the resultingradiation to a photodetector analyzer which performed the quantitativeanalysis.

The magnitude of the absorption peak is directly related to theconcentration of glucose. Suitable analyzers include modified FourierTransform Infrared (FTIR) spectrometers with chemometric softwarepackages. Those are available from the PerkinElmer Corporation(Wellesley, Mass.) and Thermo Nicolet Company (Madison, Wis.).

The signal was digitized and the concentration of conjunctival plasmaglucose determined by chemometric analysis algorithms with comparison ofthe unknown value with a standard reference to determine theconjunctival plasma glucose value. Blood was acquired and plasma glucosemeasured with conventional laboratory analysis using a Beckman analyzersystem.

The mean value of conjunctival plasma glucose was 101.2 mg/dl and acorrelation coefficient of 0.94 was achieved when compared to physicalvalues by laboratory testing. The FTIR used allows evaluation of allincident wavelengths. The signal processing of the FTIR system canselect for the final analysis the wavelength related to the substance ofinterest. Various substances of interest such as glucose, cholesterol,ethanol, can then be evaluated by using the different algorithms foreach substance incorporated in the FTIR system.

Alternatively, a custom made system, as described in the “overall setup”above, was constructed using the above light source and selectivebandpass filters centered around 2100 nm (available from CVI LaserCompany, Albuquerque, N. Mex.) for selecting the wavelength for glucose.This alternative embodiment, provides a lower-cost and more compactsystem, but is capable of measuring only one substance of interestaccording to the wavelength selected.

In-vitro calibration models available commercially can be usedaccurately and precisely as a reference since there is no backgroundinterference. However, a simplified calculation and statistical methodcan be achieved since the conjunctiva/plasma sample obeys Beer-Lambertlaw and the background variables are eliminated. The resulting radiationacquired from the conjunctiva corresponds directly to plasmaconstituents. A quantitative measure of the glucose concentration usingthe resulting absorption intensity can be provided upon calculationusing Beer-Lambert's law.

In addition, an in-vivo calibration method is used. The concentration ofplasma glucose is obtained by invasive means and analyzed in theconventional laboratory setting. The range of glucose levels of usualinterest in clinical practice (40 to 400 mg/dl) obtained invasivelycreates a reference database, which is then correlated to the resultingradiation obtained using conjunctival plasma. Considering a stableoptical system as the conjunctiva/plasma interface, the amount ofincident radiation (known) and the subsequent reflected radiation(measured) can be calculated for each wavelength related to thesubstance measured creating then a reference line. The concentration ofthe substance of interest is then determined by correlating thepredicted value with the acquired (unknown) value using thepredetermined calibration line.

An alternative embodiment and experiment involved using Attenuated TotalInternal Reflection technique and incident radiation in the 9,000 to10,000 nm wavelength region. This spectral region has high correlationwith glucose and is strongly absorbed by glucose while avoidingabsorption by interfering constituents. However this region is not usedbecause large amounts of energy are needed which can cause damage to thetissue. The large amount of energy is needed because the sample ofinterest (glucose) is located deep and the far-infrared energy isreadily absorbed by interfering constituents. Thus the radiation energydoes not reach the substance of interest (glucose) present deep in thetissues.

Contrary to that, in the present invention a low power far-infraredincident radiation was used due to the insignificant absorption due tothe characteristics of conjunctiva/plasma interface (as disclosed in theinvention) and the plasma with glucose is present in the surface. Thus,no damage or discomfort was elicited during measurement. Theconjunctiva/plasma interface allows measurement to be done in thisregion of the wavelength spectrum because the substance beinginterrogated is already separated and present in plasma in the surfaceof the sample.

FIG. 87 shows a schematic block diagram of one preferred embodiment ofthe present invention with wireless transmission of information to anexternal receiver. The apparatus includes a sensor head 2352 which has alight source 2354 such as LED and a light collector 2356 such as anoptic fiber cable which is connected to a photodetector 2358. Radiationis transmitted from the source 2354 and directed at the plasma interface2330, between the conjunctiva 2320 and sclera 2316. The resultingradiation is reflected back and collected by collecting optic fiber 2356and transmitted to photodetector 2358. The signal is then converted todigitized information by the A/D converter 2360 and sent to the RFtransceiver 2362 with the signal 2366 being transmitted to a remotelyplaced RF transceiver 2364.

The signal is then fed into the processor 2368 and memory 2376 whichcalculates the concentration of the substance of interest 2350 which issubsequently visualized in display 2370. The processor can also activatean alarm and audio transmitter 2372 that can alert the user aboutabnormal measurement levels and control the delivery of medicationthrough delivery device 2374. The delivery device 2374 can include:contact lens dispensing systems, iontophoresis-based dispensing systems,infusion pumps as insulin infusion pump, glucagon pump for injection ofglucagon when glucose levels are below 55 mg/dl, drug infusion devices,inhalers, and the like. The processor 2368 can make adjustments fordelivery of medication through delivery device 2374 according to theidentification or concentration of the substance of interest 2350.

FIG. 88 shows the front surface of the eye with cornea 2378, iris 2382,and conjunctival vessels 2380. The upper 2384 and lower 2386 eyelidswere pulled away to show the conjunctival lining 2320 covering the eyesurface and the substance of interest 2350 present in the surface of theeye. Most of the conjunctival area 2320 is hidden in the eyelid pocketboth superior and inferior and not observable by an external viewer.

FIG. 89(A) shows schematically a reflectance measuring system 2388encased in the contact device 2390, the combination of which is referredto herein as a measuring Intelligent Contact Lens (ICL). The measuringICL is placed in the eyelid pocket 2392 in apposition to theconjunctival lining 2320. The measuring ICL includes a sensor head 2314with light source 2394 and light detector 2396, RF transceiver 2402 andother electronics 2398 previously described.

FIG. 89(B) shows in more detail the sensor head 2314 in apposition tothe conjunctiva 2320 in the cul-de-sac 2404. The radiation emittedinteracts with the substance of interest 2350 present underneath theconjunctiva 2320. Source 2394 and detector 2396 are mounted adjacent toeach other in away that light from the source 2394 reaches the substanceof interest 2350 and is received by the detector 2396.

FIG. 89(C) shows a cross-section view of the eye and eyelid 2410 withthe measuring ICL 2400 and its light source 2394 and light collector2396 in apposition to the cul-de-sac 2404 of the conjunctiva 2320 whichis free of blood vessels but has plasma 2330 collected underneath. FIG.89(C) also shows another position for light source 2394 a and collector2396 a as in apposition to the bulbar conjunctiva 2406.

FIG. 89(D) shows a bird's eye view of the eye surface with cornea 2378,iris 2382, conjunctival vessels 2380, and measuring ICL 2400 inapposition to the conjunctiva 2320 and substance of interest 2350. Thethickness of the measuring ICL 2400 is preferably less than 5 mm.

The contact device or measuring ICL 2400 allows appropriate interfacewith the sample in a reproducible location and with a reproducibleamount of pressure and temperature on the sample surface. Normal eyelidsexert a stable amount of pressure against the measuring ICL 2400 whenthe eyelid 2410 is in a relaxed state, meaning without squeezing theeyelids. The pressure applied by the eyelid 2410 in the resting state isfairly constant and equal in normal subjects with a horizontal force of25,000 dynes, a tangential force of 50 dynes and pressure of 10 Torr.Muscles in the body can enlarge and become stronger by means ofcontinuous exercising such as in body building. Contrary to that, themuscles in the eyelids have a special characteristic and do nothypertrophy by continuous blinking or eyelid exercising. The muscles inthe eyelid remain with similar contractility and force throughout lifeunless affected by a disease. This similar and stable eyelidcontractility and tone allows an ideal apposition of a source detectorpair to the tissue surface. Positioning of the conjunctiva 2320 inapposition to the sensor head 2314 with the source-detector pair can bedone naturally by the eyelid which leads to great reproducibility andreproducible degrees of pressure with very low inter- andintra-individual variability.

The eyelid pocket 2420 also provides good reproducibility as far aslocation of the measurement since the measuring ICL 2400 can be made tofit a particular pre-determined area of the eyelid pocket 2420 allowingto reproduce the same location for measurement. The eyelid structuralarrangement provides the only superficial area in the body in which atrue pocket is formed creating a natural confined environment in thesurface of the body by said pocket. The conjunctiva as mentioned is athin homogenous tissue located in a naturally confined area of the bodyforming a natural pocket and the lens dimensions can assure that thesame site is taken for different measurements and centered on areas ofhigh plasma 2330 concentration and minimal blood vessels such as in thelower part of the cul-de-sac 2404. Alternatively, the light 2302 can bedirected to any point in the conjunctiva 2320.

The embodiments of the present invention provide a reproducible andstable degree of pressure and reproducible location which is achievednaturally according to the morphology and physiology of the eye andeyelids.

A contact device for placement on the surface of the eye and preferablyin the eyelid pocket as shown in FIG. 101B was used. The contact devicepreferably contains an infrared LED (available from PerkinElmerCorporation) as a light source. Infrared LEDs (wavelength-specific LEDs)are the preferred light source for the embodiment using a contact devicebecause they can emit light of known intensity and wavelength, are smallin size, low-cost, and the light can be precisely focused in a smallarea of the conjunctiva. By using an infrared LED that emits a narrowbandwidth of radiation no filters are need to be coupled with thephotodetector.

Alternatively, a miniature selective filter that transmits light withinthe 2,100 to 2,200 range of wavelengths is incorporated with thephotodetector. The selective filter transmits wavelength whichcorresponds to absorption by glucose.

The preferred photodetector included a semiconductor photodiode with a400 μm diameter photosensitive area coupled to an amplifier as anintegrated circuit. The photodetector has spectral sensitivity in therange of the light transmitted. The photodetector receives an attenuatedreflected radiation and converts the radiation into an electricalsignal. The photodetector is connected to a low-power radio-frequencyintegrated circuit and the electrical signal is converted into an audiosignal and transmitted to an external receiver.

An alternative embodiment used an A/D converter and a digital RFintegrated circuit built in the contact device. The RF circuit thentransmits the analog or binary signal corresponding to the intensity ofradiation (resulting radiation) reflected from the conjunctiva/plasmainterface. The remote RF transceiver receives the signal and sends it toa processor for signal processing and calculation of the concentrationof glucose using a predetermined calibration reference. The detectoroutput data is correlated to blood glucose levels using FTIR andstatistical analysis previously described. Although one LED wasdescribed, multiple miniature LEDs can be used as light sources forsimultaneous measurement of multiple substances using multiple pairsource/detector.

Besides active RF transmission, passive RF devices built-in in thecontact device can be used and receive the signal from the sensor. Anexternal radiating antenna emits the excitation energy which powers thecontact device. Such passive RF devices includes paper thin inductiveand capacitive designs, for example Performa tags available from CheckPoint Systems, Inc. Thorofare, N.J. and BiStatix tags available fromMotorola Inc., Schaumburg, Ill.

FIG. 90 shows a schematic block diagram of one preferred transmissionmeasuring apparatus of the present invention. In an exemplaryembodiment, the system includes a source of light 2430 which emits lightat a plurality of different wavelengths and a photodetector 2440 fordetecting light 2432 emitted from said source 2430. The source 2430 andthe detector 2440 are arranged diametrically opposed to each other andpreferably including a forceps configuration. The arrangement is suchthat the light output 2432 from the source 2430 interacts with the eyefluid and substance of interest 2350 before being collected by thedetector 2440. The resulting transmitted radiation 2434 includes theemitted radiation less the back scattered and absorbed radiation plusany forward scattering radiation. Since in the present invention thereis insignificant scattering due to interfering constituents, theresulting radiation 2434 is the known emitted radiation less theabsorbed radiation which corresponds to the substance of interest 2350.The resulting radiation 2434 is collected by the detector 2440 andcontains the spectra of the eye fluid at each of the selectedwavelengths. Since in the present invention the scattering isinsignificant and there is a high signal, a small number wavelength isrequired and the resulting spectra relates to the substance of interest2350. The resulting transmitted spectra is then converted by the A/Dconverter 2436 into digital information and the spectral informationobtained is sent to the processor 2438 for spectral analysis todetermine the concentration of the substance of interest 2350. Theprocessor 2438 can be connected to a display 2442 for reporting theconcentration of the substance of interest, to an alarm system 2444 tobring attention to abnormal and ominous values and to a medicationdelivery system 2446 which delivers medication according to theconcentration of the substance of interest.

In reference to FIG. 91(A), the radiation source fiber 2448 andcollector fiber 2452 are positioned diametrically opposed to each otherso that the output of the radiation source 2448 goes through theplasma/conjunctiva interface 2450 before being received by the collector2452 and then sent to the detector (not shown). The space X from theradiation source 2448 to the collector 2452 can be changeable but isultimately fixed in order to maintain a fixed optical distance betweensaid source 2448 and collector 2452.

In one exemplary embodiment the distance X in the tip of the forcepsdevice, meaning the distance between the light source and the lightdetector is preferably 1 mm, however various optical path distances thatencompass the sample 2450 with the substance of interest 2350 can beused. The source can include the output end of an optical fiber cableconnected to a light radiation source or a plurality of radiationsources. The detector can include the receiving end of a collection ofoptical fibers connected to one or a plurality of photodetectors.

Optical fibers encased in each arm of the forceps device are preferablyused as a light delivery 2448 and light collection 2452 system for thelight source and the light detector providing a more ergonomic designfor the forceps configuration device. During measurement theconjunctiva/plasma interface 2450 is placed between the path of theoptical beam from the source 2448 to detector 2452. The output of thelight source and the input of the detector are in contact with theplasma/conjunctiva interface 2450 or in close proximity to suchinterface.

FIGS. 91(B) and 91(C) show alternative embodiments for thesource-collector pair for exemplary transmission measuring systems. FIG.91(B) shows rigid arms 2454 connecting the light source end 2448 to thelight collector end 2452 at a fixed distance X with plasma 2330interposed between the two ends 2448, 2452. Although two arms, superiorand inferior, are shown, it is understood that only one rigid arm isneeded to keep distance X as a fixed distance.

FIG. 91(C) shows an alternative embodiment in which rigid arms 2458 areconnected to semi-permeable membranes 2456. The membranes 2456 can bemade permeable only to the substance of interest 2350 which then canenter a chamber 2460 formed by the membranes 2456 and interact with theradiation emitted by the light source 2448. The membranes 2456 can becoated with permeability enhancers which can enhance the flow of thesubstance of interest 2350 to the measuring chamber 2460. Rigid ends atprefixed distance X are used to maintain light source 2448 and collector2452 at a prescribed space to define a measuring optical path length.The radiation from the source passes through the optical fiber 2448which works as a guide path to the light. The radiation then interactswith the substance of interest 2350 selectively present in the samplefluid in the chamber 2460. The resulting radiation is incident upon thelight receiving end and guided to the detector through fiber opticcollector 2452. The embodiments of FIGS. 91(B) and 91(C) are bettersuited to use as an implantable measuring system.

FIG. 92 shows schematically one of the preferred embodiments using aforceps-like probe 2470 with wired transmission of resulting radiationsignal to the processor 2468. The apparatus includes a main body housing2472 which encases the light source 2462, photodetector 2464, A/Dconverter 2466, and a processing/controlling part 2468. In thisexemplary embodiment, the light source 2462 and photodetectors 2464 canbe located in the main body 2472 away from the forceps-like probe 2470.The main body housing 2472 is connected to the forceps-like probe 2470by cable 2474 which contains fiber optics from the light source 2462 andfiber optics to the photodetector 2464. The forceps-like probe 2470configuration includes spatially separated pairs of infrared lightdelivering fibers 2476 and light collecting fibers 2478. Arms of theforceps-like probe 2470 are moveable toward and away from each other.The gap between delivering fibers 2476 and collecting fibers 2478 can beadjusted into a fixed 1 mm position by a mechanical stop part 2480.

The conjunctival tissue and plasma are placed or grasped between the twofaces of the infrared light source end 2476 and the infrared lightdetector end 2478 in the arms of the forceps 2470. The light source 2462emits radiation which is focused onto fiber optic cable 2476. Eachsource and collector pair is spaced so that light from the light source2462 and fiber optic cable 2476 passes through the conjunctiva/eye fluidinterface (not shown) and is received by the collecting optic fibercable 2478. The resulting radiation output of the collection optic fibercable 2478 is provided through a second optical interface system to athe analyzer/detector 2464 housed in the main body housing 2472 of theunit. The signal is then converted to digital information by A/Dconverter 2466 and fed into the processor 2468 for determination of theconcentration of the substance of interest.

A modified forceps probe similar to the one illustrated in FIG. 92 wasused for transmission measurements. Conjunctiva in the cul-de-sac wasgrasped by the forceps. A halogen light source delivered radiation tothe conjunctiva coupled to the input end of optic fibers in the arm ofthe forceps. The radiation passed through the interfaceconjunctiva-plasma-conjunctiva with the optical path set at 1 mm. Thecollecting fibers sent the resulting radiation to a detector associatedwith a narrow bandpass filter centered at 2120 nm to separate theglucose band. The digitized signal was fed to the processor. Theprocessor is programmed to calculate the concentration of glucose usinga calibration line obtained by a PLS regression analysis and a 0.93correlation coefficient was obtained.

Alternatively as shown in FIG. 93(A) the measuring device 2482 can beimplanted under the conjunctiva 2320 with said device 2482 being bathedby the surrounding plasma. In such embodiment the device 2482 is encasedin biocompatible material as previously described with the opticalsurfaces encased by infrared transitive material such as sapphire orhigh-grade quartz. The system includes a main body 2484 and two armslocated diametrically opposed to each other encasing the light source2486 and detector 2488. The light detector 2488 collects the lightemitted from the light source 2486 after it interacts with the substanceof interest 2350.

During measurement the plasma 2330 located between the light source anddetector is the source medium for measuring the substance of interest2350 as shown in the enlarged view of FIG. 93(B). The dimensions of thedetector 2488 are such that allows optimal acquisition of the lightsignal emitted from the light source 2486 with the detector 2488 beingreactive to the spectrum of collected wavelengths for the substance ofinterest 2350. The output signal is converted into an electrical signalwhich is then transmitted as an audio signal by RF transceiver 2490 to aremotely placed receiving unit 2492. The signal is then converted by theAID converter 2494 and then analyzed and processed by theanalyzer/processor 2498 for obtaining the concentration of the substanceof interest 2350 which is reported by display 2496, activates an audiotransmitter 2502 that can alert the user about abnormal measurementlevels, and controls the delivery of medication through a medicationdelivery device 2504 according to said measurement. The system canalternatively include a detector and, A/D converter in the main bodywith the output signal of the detector being received by the AIDconverter which converts the signal into digital information which istransmitted by RF transceiver to remotely placed RF transceiver.

Alternatively as shown in FIG. 94 the measuring device 2500 canpenetrate the conjunctiva 2320 with one of its arms 2508 locatedunderneath the conjunctiva lining and the other arm 2506 located abovethe conjunctival lining 2320. The conjunctiva 2320 can be easilypenetrated with a very mildly sharp point or even a blunt end. Light isemitted through the conjunctiva 2320 by arm 2506 and collected by theopposing arm 2508. The conjunctiva is the only superficial area in thebody that an incision can be done using only one drop of topicalanesthetic. Although, less desirable, a reflector for infrared light canbe implanted under the conjunctiva.

A further alternative embodiment as shown in FIG. 95(A) includes aforceps 2510 configuration to be used for grasping the edge of theeyelid 2410, shown in a cross-section of the eye and eyelid. The forceps2510 of FIG. 95(A) is shown in the enlarged view of FIG. 95(B) andincludes light source 2514 such as for example light emitting diodes oroptic fibers in apposition to the red palpebral conjunctiva 2512 toradiate the conjunctiva/plasma interface 2310 and detectors 2516positioned on the opposite external surface of the eyelid 2410 inapposition with the eyelid skin 2518. Detectors 2516 collect theresulting transmitted radiation which was directed through the eyelid2410.

Eyelid 2410 is an ideal alternative for measurement since said eyelid2410 is highly vascularized and one surface 2512 is transparent withplasma 2330 present while the opposing surface 2518 is comprised of aunique type of skin. Although there is interaction of the radiation withskin, which as described can be an important source of errors, the skinof the eyelid is uniquely fit for measurements because of itscharacteristics.

The skin 2518 covering the lower eyelid 2410 is the thinnest skin in thewhole body. The skin 2518 of the eyelid 2410 is also the only skin areain the body which there is no fat layer. Since fat absorbs significantamounts of radiation over an important portion of the glucose absorbancespectrum, there is a significant reduction of signal when the substanceof interest 2350 is glucose. This interference by the presence of a fatlayer does not occur in the skin 2518 of the eyelid 2410.

This can be easily observed by pinching the skin of the lower eyelid.One can then easily feel that only a very thin skin is grasped. The samegrasping in any other part of the body will show that a much thickeramount of skin is pinched. Those characteristics, contrary to the skinin the rest of the body, enable the acquisition of a good signal tonoise ratio. However, the preferred way of the present inventionincludes complete elimination of the skin as source of errors andvariability.

The apparatus of this alternative embodiment 2510 can include a manual,spring, or automatic adjustment system for engagement and positioning ofthe device at the edge of the eyelid 2410, right above the eyelashes2522. The apparatus can also include a fixed predetermined space betweensource 2514 and detector 2516 according to the individualcharacteristics of the eyelid 2410. Although one means to grasp theeyelid was described, it is understood that a variety of manual orautomatic assemblies to grasp the edge of the eyelid 2410 can be used.In this embodiment, clinical calibration instead of analyticalcalibration can be used and the device 2510 is calibrated according tothe fairly constant skin and tissue characteristics of said eyelid skin2518.

As shown in FIG. 96, the forceps probe 2520 is grasping the bulbarconjunctiva and plasma interface 2310. The forceps probe 2520 can bewirelessly connected with the main body housing 2524 via RF transceiver2526 in the probe 2520. The forceps probe 2520 can include the lightsource 2528 and detector 2530, optic fibers 2532 for directing radiationand optic fibers 2534 for collecting radiation which has interacted withthe substance of interest 2350 present in the plasma 2330. The signal2536 is wirelessly transmitted to the RF transceiver 2538 in the mainbody housing 2524. The main body 2524 also encases the display 2540, andmemory and processor 2542 which makes a spectrum analysis of thecollected resulting radiation and determine the concentration of thesubstance of interest 2350. Conventional statistical analysis and modelscan be used for the determination of concentration of the substance ofinterest 2350, but said analysis and models are simplified and lessprone to errors since the majority of interfering constituents areeliminated in accordance with the principles of the present invention.The tip of the forceps probe 2520 serves to receive theconjunctiva/plasma interface 2310 with the substance of interest 2350 tobe measured. The position of the forceps arms are arranged to adjust theproper spacing with respect to the conjunctiva/plasma medium 2310 toremain stable during the measurement.

A further embodiment as shown in FIGS. 97A and 97B can include aforceps-like system 2560 embedded in a contact device 2562 with two armsextending from the main body of the contact device 2562. A light source2564 and a light detector 2566 are encased in said contact device 2562and located diametrically opposed to each other, preferably at a fixeddistance. In this embodiment the bottom part of the contact device 2562lodges in the cul-de-sac 2404 of the eyelid pocket. The recess presentbetween the two arms 2564 and 2566 in the bottom part of the contactdevice 2562 captures the plasma/conjunctiva interface 2310.

In this embodiment the output of the forceps-like system 2560 can bewirelessly communicated to the receiving unit/processor 2568. Theprocessor 2568 is programmed to execute algorithm and functions neededto determine the concentration of the substance of interest 2350. FIG.97(C) shows an alternative embodiment in which the contact device 2570communicates the output by a micro wire 2572 connected to a receiver2572 a and to a processor and display (not shown). Radio transceiver2572 a can include an adhesive patch that is attached to the skin. Themicro wires 2572 can comfortably exit the eye and be connected with theadhesive transceiver 2572 a. The signal can then be transmitted toanother receiver for further processing and display. Alternatively,transceiver 2572 a can be comprised of processing and display means. Abooster or transceiver placed around the ear can also be used to receivethe signal from either contact device 2750 (wired) or 2400 (wireless) onthe eye. Contact device can be used for measurement of temperature aswell as evaluation of the concentration of the substance of interest.

FIG. 98(A) shows the measuring ICL 2580 in which only the tip of thesensor 2574 penetrates the conjunctiva 2320. The tip 2574 is bathed bythe plasma 2330 with the substance of interest 2350 in direct contactwith the sensor tip 2574. The tip 2574 can include an electrochemicalsensor, an optical sensor, or the like. In addition, fiberoptic optodescan be used in the tip 2574 to continuously monitor pH, carbon dioxidepartial pressure, and oxygen partial pressure. The main body 2576 of themeasuring ICL 2580 is located in the eyelid pocket 2420 and restsagainst the conjunctiva 2320. The signal 2578 can be wirelesslytransmitted to an external receiver 2580. This embodiment provides acost-effective away of achieving the measuring function since there isno need for the main body 2576 to be in intimate apposition to theconjunctiva for capturing flow of plasma 2330 with the substance ofinterest 2350 in case of using electrochemical techniques.

The main body 2576 can be made with inexpensive biocompatible polymersthat do not need to intimately interact with the surface of theconjunctiva 2320. The flow of plasma occurs directly into the sensingmeans of the tip 2574. The tip 2574 of the sensor is placed in intimateand immediate contact to the plasma 2330 flowing from the blood vessels.FIG. 98(B) shows a cross-sectional view of the eye, eyelid 2410, andeyelashes 2522. The measuring ICL 2580 is in the eyelid pocket 2420. Thetip 2574 of the sensor penetrates the conjunctiva 2320 and is bathed byplasma 2330 and substance of interest 2350 in the cul-de-sac area 2404.

FIG. 99(A) shows an alternative embodiment in which the sensor 2582 ishoused in an intraocular lens 2590. The measuring intraocular lens 2590includes a transparent main body 2584 usually with optical properties.The measuring intraocular lens 2590 can be used as a replacement for thediseased natural lens of the eye during a cataract operation, an opticalsurface placed in addition to the natural lens of the eye for correctionof refractive errors, and the like. The measuring intraocular lens 2590is implanted surgically inside the eye. This intraocular lens 2590 thenis bathed by the aqueous humor 2588 with its various substances ofinterest 2350.

Although this alternative embodiment requires a surgical procedure andthe substance of interest 2350 is present in diluted quantities, thisembodiment allows direct contact of the aqueous humor 2588 with thesensor surface 2582. Sensor 2582 can include electrochemical sensors,optical sensors, chemical sensors, or the like. The sensor 2582 can beencased in the main body 2584 and acquire the signal corresponding tothe substance of interest 2350 as previously described.

The signal is then transmitted to a remote receiver and processor (notshown) for identification and determination of the concentration of thesubstance of interest. The apparatus can include a main body 2584 withor without optical properties with the sensor 2582 encased in said mainbody 2584 and the haptics 2586 of the intraocular lens 2590 being usedas antennas. The sensor 2582 can also be attached to one of the haptics2586.

FIG. 99(B) shows a cross section of the eye with the intraocular lens2590 implanted and placed in the capsular bag. The main body 2584 withsensor 2582 is positioned in the center with the haptics 2586 providinga supporting function. The substance of interest 2350 present in the eyefluid 2588 interacts with the surface of the sensor 2582.

FIG. 99(C) shows an alternative embodiment with modified main body 2592and haptics 2586. This modified main body 2592 houses in its peripherylight source 2594 and light collectors 2596 diametrically opposed toeach other. The substance of interest 2350 is present in the fluid 2588that bathes the lens 2600 and the recess 2598 formed between lightsource 2594 and collector 2596. In this embodiment the sensor system canbe powered using active or passive means including electromagneticcoupling, photoelectric cell using energy from the environment,biological sources, and the like.

Alternatively as shown in FIG. 99(D), an intra-vitreal implant plate2610 can be used. The sensor 2612, includes optical, electrochemicalsensors or the like. The sensor 2612 can be placed in the vitreouscavity 2614 inside the eye using an incision around the pars plana 2616area of the eye which is the area between the ciliary body 2618 and theretina 2620. In this embodiment the sensor 2612 is encased in abiocompatible plate 2610 and inserted inside the eye in the vitreouscavity 2614. The plate 2610 is secured with a stitch to the sclera andthe sensor 2612 is in contact with the vitreous humor of the eye.

Besides reflectance and transmission spectroscopy, the methods andapparatus of the present invention provide optimal detection using otherregions of the electromagnetic spectrum. Another preferred embodimentincludes measurement of substances in eye fluid and plasma usingfar-infrared spectroscopy and will be described in detail below. Forexample but not by way of limitation two other techniques that can useother regions in the electromagnetic spectrum will be briefly described:radio wave impedance and fluorescent techniques.

Now with reference to FIG. 100(A), the temperature and far-infrareddetection ICL 2650 includes a housing 2652 having the shape of a contactdevice to engage the surface of the eye and an infrared sensor 2654which detects infrared radiation from the eye. The far-infrareddetection ICL 2650 is preferably placed in the eyelid pocket 2420 whichallows intimate and stable contact with the tissue in the eye.

Referring to FIG. 100(B), an infrared sensor 2654 is placed inapposition to the conjunctiva 2656 bulbar or palpebral, but preferablythe bulbar conjunctiva in apposition to the sclera. Alternatively theface of the sensor 2654 can be placed in apposition to the red palpebralconjunctiva 2656, with said conjunctiva containing blood vesselssuperficially and being in apposition to the eyelid. The heat radiation2660 emitted by the plasma 2658 in apposition to the sclera 2659 travelsdirectly to the infrared sensor 2654. The heat radiation 2660 passesonly through the thin conjunctiva 2656 with said infrared emission 2660not being absorbed by the conjunctiva 2656.

The infrared emission 2660 from the blood/plasma 2658 in theconjunctival vessels is collected by the sensor 2654 which can includean infrared sensor or other conventional means to detect temperature oncontact. The temperature sensor 2654, preferably a contact thermosensor,is positioned in the sealed environment provided by the eyelid pocket2420, which eliminates spurious readings which can occur by accidentalreading of ambient temperature. The sensor 2654 can measure theintensity of the infrared radiation 2660.

For example, a thermopile sensor which converts the infrared radiation2660 into an electrical signal can be used or a temperature sensor as athermistor-like element. The sensor 2654 coupled with a filter thatcorrelates with the substance of interest converts said infrared energy2660 into an electrical signal. The signal is then transmitted bywireless or wired transmission to a processor (not shown) whichcalculates the concentration of the substance of interest.

FIG. 100(C) shows a schematic block diagram of one preferredfar-infrared spectroscopy measuring apparatus of the present invention.The apparatus includes a thermal infrared detector 2654 which has afilter 2662 and a sensing element 2664 with said sensing element 2664being preferably a thermopile and responding to thermal infraredradiation 2660 naturally emitted by the eye. A variety of infraredsensors responsive to thermal radiation can be used as sensor 2664besides a thermopile, such as for example, optoelectronic sensorsincluding thermistor-based infrared sensor, temperature sensitiveresistor, pyroelectric sensors, and the like, and preferably thinmembrane sensors. The detector 2654 faces the conjunctiva 2656 and ifthe face of the detector 2654 is encased by the housing 2652 material,said material is preferably transparent to infrared radiation.

The far-infrared radiation 2660 emitted by the conjunctival blood/plasma2658 (within the spectrum corresponding to thermal radiation from thebody; from 4,000 to 14,000 nm) is partially absorbed by the substance ofinterest 2350 according to its band of spectral absorption and which isrelated in a linear fashion to the concentration of said substance ofinterest 2350. For example in the thermally sealed and thermally stableenvironment in the eyelid pocket 2420 (FIG. 102A), at 38 degrees Celsiusspectral radiation 2660 emitted as heat by the eye in the 9,400 nm bandis absorbed by glucose in a linear fashion according to the amount ofthe concentration of glucose. The resulting radiation fromconjunctiva/plasma 2658 is the thermal emission 2660 minus the absorbedradiation by the substance of interest 2350.

This resulting radiation enters the infrared detector 2654 whichgenerates an electrical signal corresponding to the spectralcharacteristic and intensity of said resulting radiation. The resultingradiation is then converted into digital information by converter 2666.The signal 2671 is then transmitted by RF transceiver 2668 to a remotelyplaced receiver 2670 connected to a processor 2672.

The processor 2672 then calculates the concentration of the substance ofinterest 2350 according to the amount of thermal energy absorbed inrelation to the reference intensity absorption outside the substance ofinterest band. The output can be adapted to report the value on adisplay 2674, activate an audio transmitter 2676, and control dispensingmeans 2678 for the delivery of medications.

A variety of filters can be used to include the spectral region ofcorrelation to the substance of interest. The apparatus can also includea heating induction element and cooling element as well as lightradiation and collection means (not shown) to create an integratedfar-infrared and near-infrared system. The front surface of contactdevice can have a coating to increase energy transfer in the spectralregion of interest.

In reference to FIG. 100(D), the temperature and far-infrared detectionICL 2651 includes a housing 2653 having the shape of a contact device toengage the surface of the eye and a dual infrared detector arrangement2654 which is selected to detect far-infrared radiation corresponding tothe substance of interest, and sensor 2655 which is used as-a referenceand detects radiation outside the wavelength corresponding to thesubstance of interest. Filters are used to select a wavelength ofinterest and a reference wavelength to calculate the concentration ofthe substance of interest. The far-infrared detection ICL 2651 ispreferably placed in the eyelid pocket 2420 which allows intimate andstable contact with the tissue and source of heat as found in the eyesurface.

A contact device with a germanium coated selective filter coupled to athermopile detector was constructed and used to non-invasively measureconjunctival plasma glucose emitted as thermal emission from the eye.The preferred embodiment comprised an arrangement which included thethermopile coupled to the germanium coated selective filter for passinga wavelength corresponding to a wavelength of high correlation with thesubstance of interest.

For this exemplary measurement of glucose, wavelength centered around9,400 nm (glucose band) was used. There is a prominent absorption peakof glucose around 9,400 nm due to the carbon-oxygen-carbon bond in itspyrane ring present in the glucose molecule. The contact device filtersystem allowed passage of the glucose band which is used as a referencemeasuring point while simultaneously measuring thermal energy absorptionoutside the glucose band. The thermal energy absorption in the glucoseband by plasma glucose is spectroscopically determined by comparing themeasured and predicted radiation at the conjunctival surface.

The predicted amount of thermal energy radiated can be calculated by thePlanck distribution function. The absorption of the thermal energy inthe plasma glucose band is related in a linear fashion to glucoseconcentration and the percentage of thermal energy absorption isarithmetically converted to plasma glucose concentration. One preferredembodiment includes a dual detector arrangement in the same contactdevice. One detector has a filter for reference and the other has anarrow band pass filter for the substance of interest. The ratio of thetwo wavelengths is used to determine the concentration of the substanceof interest.

The system and method of the invention using the conjunctiva/plasmainterface solves all of the critical problems with the technique ofusing thermal emissions by the body for non-invasive analysis. One ofthe critical issues is related to the fact that the signal size of humanthermal emissions is very small as occurs in the skin, mucosal areas,tyrnpanic membrane and other surface areas in the body. This inabilityof acquiring a useful signal is in addition to the other drawbacks andinterfering constituents previously mentioned. The present inventionusing its preferred embodiments achieves a high signal and correlationby providing a unique place in the body that combines a thermally sealedand stable environment as in the eyelid pocket with a contact devicethat provides direct contact of detector to the source of heat (bloodand plasma) associated with measurement of core temperature, large areaof the contact sensor to detector, no interfering constituents, and withactive heat transfer from the tissue to the detector.

In addition, due to the characteristics of the conjunctiva/plasmainterface as described and high signal obtained, other novel techniquescan be easily achieved. One of them includes the use of a calibrationline as another preferred embodiment. The concentration of plasmaglucose can be obtained by invasive means and analyzed in the laboratorysetting. The range of glucose levels of usual interest in clinicalpractice (40 to 400 mg/dl) obtained invasively creates a referencedatabase to be correlated to the intensity of radiation obtained usingthe contact device in the eyelid pocket of the present invention.Planck's function can be used to convert temperature to intensities.This invasive reference is done for each clinically useful level oftemperature, for example 35 to 41 degrees Celsius. For example, at 37degrees Celsius, the concentration of glucose (e.g. 100 mg/dl was theglucose level) measured invasively correlated to the spectral intensityvalue detected at 9,400 nm by the contact device. The concentration ofthe substance of interest is then determined by correlating thepredicted value with the acquired (unknown) value using thepredetermined calibration line.

Alternatively, a temperature sensor can be included in the contactdevice and provide a correction factor according to the level oftemperature thus avoiding a calibration table that requires differentlevels of reference temperature. Processing applies automatically thereal time value of the temperature to determine the concentration of thesubstance of interest. Yet in another alternative embodiment, inputmeans can be provided that allows the user to input the temperaturevalue manually with processing applying that value when calculating theconcentration.

Alternatively, a heating element is incorporated in the contact device.The increase in temperature creates a reference measurement which iscorrelated with the measurement achieved using the natural thermalemission. Moreover, a bandpass filter can be used to select oneparticular wavelength such as 11,000 nm that is used as a reference andcompared to the wavelength of the substance of interest creating a dualdetector system with narrow bandpass interference filter. Onedetector/filter passing a narrow range of radiation centered at 9400 nmand a second detector/filter passing radiation centered at 11000 nm.Selective filters are used to adjust passage of radiation related to thespectrum region of interest, in the case of glucose from 9,000 to 11,000nm. For detection of ethanol levels the 3,200 to 3,400 nm region of thespectrum is selected. Alternatively, a heating and cooling of thesurface of the conjunctiva can-be used and the thermal gradient used todetermine the concentration of the substance of interest.

Another preferred embodiment includes the use of Beer-Lambert's lawin-vivo to determine the concentration of the substance of interestusing thermal emissions. In other parts of the body, with the exceptionof the eyelid pocket and surface of the eye, various natural phenomenaand structural characteristics occur that prevent the direct in-vivo useof Beer's law for the determination of the concentration of thesubstance of interest:

-   -   1. The optical path length cannot be determined. In standard        spectroscopic calibration and in-vitro measurement, the optical        path length comprises the length traversed by light in the        sample being evaluated such as for example contained in a        cuvette. In any part of the body the thermal emission travels an        unknown path from the origin of heat deep in the body until it        reaches the surface.    -   2. Self-absorption. This relates to the phenomena that deep        layers of tissue selectively absorb wavelengths of infrared        energy prior to emission at the surface. The amount and type of        infrared energy self-absorbed is unknown. At the surface those        preferred emissions are weak due to self-absorption by the other        layers deriving insignificant spectral characteristic of the        substance being analyzed. Self-absorption by the body thus        naturally prevents useful thermal emission for measurement to be        delivered at the surface.    -   3. Thermal gradient. The deeper layers inside the body are        warmer than the superficial layers. The path length increases as        the thermal gradient is produced. This third factor in addition        to the two described above to further prevent undisturbed        natural body heat to be used for determination of concentration        of substances. Moreover, there is excessive and highly variable        scattering of photons when passing through various layers such        in the skin and other solid organs. This scattering voids the        Beer-Lambert law due to radiation that is lost and not accounted        for in the measurement associated to an unknown extension of the        optical path length and other thermal loss.

The characteristics of the conjunctiva/plasma interface as describedfits with and obeys Beer-Lambert's law. The conjunctiva is a transparentsurface covering a clear solution (plasma is clear which preventsmultiple scattering) which contain a substance to be measured such asglucose. Due to the unique geometry of the conjunctiva/plasma interface,the method and apparatus of this preferred embodiment provide for a keyvariable in-vivo that allows direct use of Beer-Lambert's law, which isthe optical path length. The embodiment provides the equivalent of anin-vivo “cuvette” since the conjunctiva/plasma interface thickness (d)is stable for each location in the eye. The mid to inferior third of theundisturbed bulbar conjunctiva/plasma interface measures 100 μm.Dimensions (d) are similar for each area but can vary greatly from areato area reaching a few millimeters in the lower parts and 20 micrometersin the upper third of the conjunctiva/plasma interface.

One face of the cuvette is the conjunctiva surface and the other face isthe sclera with clear plasma in between. The sclera has tissueinsulation characteristics that make this surface of the cuvette as theorigin of the thermal radiation. The sclera accomplish that because itis a tissue completely avascular, white and cold in relation to theconjunctiva/plasma interface which has the heat source coming from theblood and plasma. The efficiency with which glucose absorbs light iscalled extinction coefficient (E). E is measured as the amount ofabsorption produced over 1 cm optical path length by 1 molar solution.Then, the radiation absorbed or Absorbance (A=log I_(o)/I) by thedissolved material (e.g., glucose) equals the molar extinctioncoefficient (E) of the substance of interest for the particularwavelength employed times the concentration (c) times the optical pathlength (d). The equation can be written as:A=log(I _(o) /I)=E·c·d  (1)And rewritten to determine the unknown concentration (c)c=A/E·d  (2)

where I_(o) can be measured as the original intensity of the incidentradiation, I is the transmitted intensity through the samplecorresponding to the substance of interest according to the wavelengthselected and can be detected with a photodetector.

The other two interfering problems above, self-absorption and thermalgradient, are also eliminated providing the accuracy and precisionneeded for clinical application. There is no self-absorption by tissues.The radiation (heat) is generated by the local blood/plasma flow and theonly tissue traversed is the conjunctival lining which does not absorbthe radiation. There is no other tissue interposed in the path fromsource (heat in the eye surface) to detector. In addition, there are nodeep or superficial layers interposed and since the source of heat(blood/plasma) is in direct apposition to the detector, thermal gradientis insignificant.

Filters can limit the wavelength (thermal radiation) to the desiredrange. It is understood that multiple filters with different wavelengthselectivity can be used for the simultaneous measurement of varioussubstances of interest. For example a selective filter allows passage of9,400 nm band when the substance of interest is glucose. The incidentthermal energy traversing the detector, for example a thermopiledetector, is proportional to the glucose concentration according to acalibration reference. Alternatively filters can be used to select awavelength of interest and a reference wavelength to calculate theconcentration of the substance of interest as previously described. Yetalternatively the ratio of the concentration of water to the substanceof interest can be used to determine the concentration since theconcentration of water is known (molecular weight of water is 18 forminga 55.6 molar solution with water band at 11000 nm).

The same principles disclosed above can be used for near-infraredtransmission measurements as well as for continuous wave tissueoximeters, evaluation of hematocrit and other blood components. Thesubstance of interest can be endogenous such as glucose or exogenoussuch as drugs including photosensitizing drugs.

Photosensitizing agents are a class of drugs used in PhotoDynamicTherapy (PDT). PDT relies on photoactivation of an exogenouslyadministered photosensitizing drug. A variety of cancers and age-relatedmacular degeneration can be treated in this fashion. Those drugs areinjected in the circulation of a patient and activated by light afterreaching the target organ. The time point between the injection of thephotosensitizing drug and exposure to light is critical. However,previously there was no way to determine the time according to real-timemeasurement of the concentration of the drug in the patient.

For example, in the treatment of macular degeneration in the eye, anarbitrary time of 15 minutes from the time of injection to applyinglight is chosen for all patients using verteporfin. This time relates toan attempt to achieve optimal concentration of the drug in the targettissue and presumes that all patients will have the same amount of thedrug in the eye after 15 minutes. However, substantial variation inpharmacodynamics and pharmacokinetics of the drug can occur from patientto patient preventing an optimum time from injection to photoactivationto be achieved without actually measuring the concentration of the drugin plasma. If photoactivation is done too early it can damage thetissue, and if done too late has no therapeutic effect.

By knowing the concentration of the drug an optimum time forphotoactivation can be achieved in addition to adjusting the amount ofenergy delivered in accordance to the concentration of the drug. In thecase of the eye, an accurate concentration of the drug in the retina canbe achieved by measuring the concentration of the drug in theconjunctiva. In addition, measurement of drug concentration in plasmapresent in the eye accurately reflects the concentration of the drug inother parts of the body.

The concentration of the drug can be determined in various ways. In thecase of the eye using the drug verteporfin, photoactivation is achievedusing a wavelength of 689 nm. A light source providing the samewavelength (689 nm) could be used but has the risk of photoactivationand damage of tissue. It is preferably then that an infrared LED ofshorter wavelength, for example an AlInGaP LED, can be used to deliverradiation that interacts with the drug present in the conjunctivalplasma.

The intensity of the reflected radiation is measured by photodetectorsadjusted to receive the peak absorption radiation from the drug presentin the conjunctival plasma. Determination of the concentration of thedrug can be done by directly applying Beer-Lambert's law as described orcomparing the measured value against a predetermined calibration line.The calibration consists of the relationship between the physicalquantity measured to the signal obtained.

Other exemplary agents include purlytin (tin ehtyl etiopupurin) which isphotoactivated at 664 nm. A determination of concentration achieved canbe obtained in a similar manner as described for verteporfin.

Yet another exemplary agent includes lutetium texaphyrin. In this casephotoactivation is achieved using a wavelength of 732 nm. In this case alight source in the contact device, such as a LED, illuminates theconjunctiva at a wavelength of 690 nm. When illuminated at 690 nm thelutetium texaphyrin fluoresces at 750 nm. A suitable detector for 750 nmis incorporated to detect the intensity of the reflected radiation whichcan be done with the detector being in direct contact with the tissueors by non-contact means with an externally placed detector aimed at theconjunctiva.

The apparatus which is employed for single or continuous measurement oftemperature, but not for determining concentration of the substance ofinterest can include a simpler arrangement than the embodiment fordetermination of the concentration of the substance of interest. Inaccordance with this exemplary embodiment for temperature measurement asshown in FIG. 101(A), the thermal energy 2682 emitted by the eye issensed by the temperature sensor 2680 such as a miniature thermistorwhich produces a signal representing the thermal energy 2682 sensed. Thesignal is then transmitted by RF transmitter 2685 to a remotely placedreceiver 2687. The signal is then converted to digital information byA/D converter 2684 and processed by processor 2686 using standardprocessing for determining the temperature. The temperature level canthen be displayed in degrees Centigrade, Fahrenheit or Kelvin in display2688.

The processor 2686 can also control activation of ICL system 2690 fordetection of infectious agents during a temperature spike. If aninfectious agent is identified as by microfluidic systems, the processor2686 can control the delivery of antibiotics according to the infectiousagent identified, or control chemotherapy if cancer markers areidentified. Drug dispensing devices implanted in the eye (inside theglobe or under the conjunctiva) can be used to deliver drugs accordingto the signal received.

The tear punctum area and inner canthal area of the eye are importantfor measuring substances non-invasively and for the measurement of coretemperature. The punctum and inner canthal area is the hottest part ofthe body that is exposed (not in the eyelid pocket) to the environmentand that reflects core temperature. A temperature sensor can be placedagainst the inner canthal area and tear punctum with the remaining RFtransmitter and electronics placed inside the eyelid pocket.

FIG. 101 (B) shows a cross-sectional view of the eye with a temperaturemeasuring contact device 2681. The contact device thermometer includestwo miniature temperature sensors 2683, 2689, for example a passivetemperature sensor such as a thermocouple. Sensor 2689 is in appositionto the cornea facing the ambient and measuring cornea temperature.Sensor 2683 is inside the eyelid pocket and measuring core temperature.The signal from both sensors 2683,2689 is transmitted to an externalreceiver 2687.

This embodiment can be used for measurement of temperature and thedifferential used to evaluate the presence of disorders such as cancerwhich increases temperature. Although two temperature sensors are shownit is understood that only one temperature sensor on the cornea can alsobe used as well as multiple temperature sensors encased in any part ofthe contact device disclosed.

A variety of temperature sensing elements can be used as a temperaturesensor including a thermistor, NTC thermistor, thermocouple, or RTD(Resistance Temperature Detector). A temperature sensing elementconsisting of platinum wire or any temperature transducer includingtemperature sensitive resistors fabricated from semiconductor materialare also suitable. Other sensing means that can change value over timeand provide continuous measurement of temperature include:semiconductors, thermoelectric systems which measure surfacetemperature, temperature sensitive resistors in which the electricalresistance varies in accordance with the temperature, and the like.Those temperature sensors and resistance temperature device can beactivated by closing or blinking of the eye.

Alternatively, a low mass black body coupled to an optic fiber whichfluoresces according to the temperature can be used. The amount of lightis proportional to the temperature. An alternative embodiment includesreversible temperature indicators including liquid crystal MYLAR sheets.External color detectors read the change in color which corresponds tothe temperature.

FIG. 102(A) shows the far-infrared detection Intelligent Contact Lens2650 in the eyelid pocket 2420 which provides non-nvasive measurement ofthe substance of interest using natural eye emission as heat in additionto providing measurement of core temperature of the body. The sensor2654, in contact with the conjunctiva 2656 and substance of interest2350, draws thermal energy (heat) from said conjunctiva/plasma 2658 andmaximizes the temperature detection function. There is no interferencesince the heat source which is the blood/plasma flow in the surface ofthe conjunctiva 2656 is in direct apposition to the sensor 2654. Theeyelid pocket 2420 functions as a cavity since the eyelid edge 2693 istightly opposed to the surface of the eyeball 2692. The eyelid pocket2420 provides a sealed and homogeneous thermal environment. There isactive heat transfer from the conjunctiva/plasma 2658 to the sensor 2654caused by local blood/plasma flow which is in direct contact with saidsensor 2654. The opposing surface, the sclera 2659, serves as aninsulating element. The increasing surface-to-surface contact as occurnaturally in the eyelid pocket 2420 (conjunctiva surface-to-sensorsurface contact) increases the rate of heat energy 2660 transfer fromconjunctiva 2656 to temperature sensor 2654.

FIG. 102(B) shows the far-infrared detection Intelligent Contact Lens2651 in the eyelid pocket 2420 which provides non-invasive measurementof the substance of interest using natural eye emission as heat inaddition to providing measurement of core temperature of the body. Thesensor 2654 in contact with the red palpebral conjunctiva 2657 andsubstance of interest 2350 draws energy from said conjunctiva 2657 andblood vessels 2661 to maximize temperature detection function. The heatsource which is the blood/plasma flow in the surface of the conjunctiva2657 is in direct apposition to the sensor 2654. The eyelid pocket 2420functions as a cavity since the eyelid edge 2693 is tightly opposed tothe surface of the eyeball 2692.

The eyelid pocket 2420 provides a sealed and homogeneous thermalenvironment with capillary level 2661 present in the surface. There isactive heat transfer from the vessels 2661 to the sensor 2654 caused bylocal blood/plasma flow which is in direct contact with said sensor2654. The increasing surface-to-surface contact as occur naturally inthe eyelid pocket 2420 (conjunctiva surface-to-sensor surface contact)increases the rate of heat energy 2660 transfer from conjunctiva 2657 totemperature sensor 2654.

FIG. 102(C) shows an alternative embodiment illustrating a cross-sectionview of the eye with cornea 2694, upper and lower eyelids 2410, 2411,anterior segment of the eye 2696 with aqueous humor 2588 and substanceof interest 2350 in said anterior chamber 2696 of the eye. FIG. 102(C)also shows the eyes closed with the thermal sensor 2654 located on thesurface of the cornea 2694 and the substance of interest 2350 andthermal emission 2660 coming through the cornea 2694. When the eyelidsare closed (during blinking or during sleeping), the thermal environmentof the eye is exclusively internal corresponding to the core temperatureof the body. This alternative embodiment can be preferably used formeasurement of temperature or substance of interest 2350 duringsleeping.

Radio wave impedance techniques can also be used and enhanced by theprinciples of the invention. Impedance is proportional to thedifferences in amplitude and phase of the wave compared to a referencewave. Radio waves promote excitation of molecular rotation. In referenceto FIG. 103, the substance of interest 2350 interacts with the radiowave 2700 to attenuate the amplitude and shift the phase of the wavecreating a resulting wave 2702. The resulting impedance 2702 isproportional to the concentration of the substance of interest 2350which can be calculated using a conversion factor.

FIG. 103 shows the substance of interest, for example a nonionic solutesuch as glucose, which interacts with a radio wave 2700 that is passedthrough the conjunctiva/plasma interface 2310. Since there are fewinterfering elements and glucose in plasma is in relative higherconcentration compared to background, the concentration can beaccurately and precisely obtained.

Light induced fluorescence can be used since the since the plasma withthe analyte to be measured is present on the surface. A variety offluorescent techniques can also be used to identify or quantify asubstance or cellular constituent. A variety of disorders includingbacterial infection, degenerative diseases such as Alzheimer, multiplesclerosis and the like can be identified by for example emitted light orfluorescent light generated by interaction with degenerated constituents(not shown). The radiation induced fluorescence depends on thebiochemical and histomorphological characteristics of the sampleincluding presence of cancerous cells which can be opticallycharacterized in the surface of the eye and conjunctiva.

FIG. 104(A) shows a probe arrangement for reflectance measurement with awired handle 2730 which contains the fiber optic bundles for delivery ofand collection of radiation directed at the substance of interest 2350present- in the conjunctiva/plasma interface 2310. The probe can alsowork as a pen like device with the signal being wirelessly transmittedto an external receiver.

FIG. 104(B) shows a schematic illustration of another preferredembodiment using non-contact infrared detection of thermal radiationfrom the conjunctiva/plasma interface 2310. A penlight 2731 measuringdevice receives radiation 2660 which passes through filter 2733corresponding to high correlation with the substance of interest 2350and filter 2732 that works as a reference filter outside of the rangecorresponding to the substance of interest 2350. The pen 2731 containsthe electronics and processing (not shown) needed to calculate anddisplay the data. Display 2737 shows the concentration of the substanceof interest, for example the glucose value and display 2735 shows thetemperature value. FIG. 104(B1-B3) shows illustratively the differentlocations in the eye that measurement can be done, in the conjunctiva2739, in the inner canthal area and tear punctum 2741, and in the cornea2742.

FIG. 104(C) is a block diagram of a continuous measurement system of theinvention in which the infrared detector is mounted preferably in theframe of eye glasses. A head-band and the like can also be used. Thefield of view of the infrared sensor is directed at the exposedconjunctival area when the eyes are open. The continuous signal of theinfrared sensor is delivered to a RF transmitter which transmits thesignal to an external receiver for subsequent processing and display.

FIG. 104(D) shows the measuring pen 2731 coupled with a telescope orlighting system which are in line with the area from which radiation isbeing emitted from the surface of the eye. This allows precise aim andindicates the area being measured for consistency.

FIGS. 104(E) is a schematic view of the probe of pen 2731. The tip restsagainst the conjunctiva 2320 with a sensor arrangement located in arecess inside the tip of the probe. The sensor arrangement includesfilter 2662 a for the substance of interest and 2662 b that is used as areference and infrared detector 2664.

FIGS. 104(F-G) show a cross-sectional view for various positions of theprobe of pen 2731 in relation to the conjunctiva. FIG. 104(F) show theprobe resting on the conjunctiva 2320 and covered by disposable cover2665 while FIG. 104(G) shows the probe receiving thermal radiation 2660away from the conjunctiva 2320.

FIGS. 104(H-J) show in more detail some arrangements for selectingsubstance of interest according to the wavelength. FIG. 104(I) showsfilter 2662 a corresponding to the substance of interest and filter 2662b used as a reference. FIG. 104(J) shows a similar arrangement as inFIG. 104(I) with an additional temperature sensor 2667. FIG. 104(H)shows a preferred embodiment with a selection arrangement consisting ofinfrared sensor 2662 e receiving thermal radiation 2660 from conjunctiva2320 at the body temperature. Infrared sensor 2662 e has two junctions,a cold junction 2662 d and a hot junction 2662 c. The cold junction iscovered with a membrane (not shown) to reduce the amount of heatreaching said cold junction 2662 d. In addition, the cold junction 2662d is artificially cooled and thus receives the radiation from theconjunctiva 2320 at a lower temperature. The increased temperaturegradient created increases the voltage signal of detector 2662 efacilitating determination of the concentration of the substance ofinterest. Alternatively, the cold junction 2662 d is mounted surroundingthe hot junction 2662 c (not shown) and an aperture is created to directthe heat toward the hot junction 2662 c while avoiding the cold junction2662 d. The above arrangements which increase the temperature gradientin the infrared sensor helps said sensor 2662 e to remain with a highsignal since when the narrow band pass filter is placed in front of theinfrared detector the signal is decreased. Narrow band pass filters suchas found in rotatable filter 2673 are placed preferably in front of thehot junction and centered at the wavelength corresponding to thesubstance of interest. The signal can also be increased by increasingthe number of junctions in the detector and increasing the resistance. Athermistor can be incorporated to measure the temperature in the coldjunction in order to accurately measure the temperature of theconjunctiva. The probe head 2731 a of pen 2731 can include a wall (notshown) positioned between sensor 2662 c and sensor 2662 d similar to theone described in FIG. 86.

A variety of means can be used to increase the temperature gradientbetween the hot and cold junctions of a thermopile and increase thesignal including using a power source to bring the cold junction to alower temperature. Besides using thermoelectric means, contact coolingwith cold crystals or cold bodies can be used to decrease thetemperature of the sensor. When using the contact device 2400 thecooling of the cold junction cools the conjunctiva in a very efficientmanner since the conjunctiva is very thin and has a small thermal mass.When using the pen 2731 the cooling of the infrared sensor is carriedfrom the surface of the sensor to the conjunctival surface with coolingof said conjunctival surface.

Due to the characteristics of the conjunctiva/plasma interface asdescribed, with direct application of Beer-Lambert's law anddetermination of a precise calibration line, a reference filter may beeliminated. This simple and cost-effective arrangement is only possiblein a place like the conjunctiva/plasma interface. The intensity of thereceived radiation is evaluated against a predetermined calibration lineand corrected according to the temperature detected.

The characteristics of the plasma-conjunctiva interface allows a varietyof hardware arrangements and techniques to be used in order to determinethe concentration of the substance of interest as has been described.One preferred embodiment is shown as a cross-sectional view in FIGS.104(K-1). The arrangement of probe head of pen 2731 includes a rotatablefilter 2763 for measurement of various substances according to selectionof the appropriate filter corresponding to the substance of interest.FIG. 104 (K-2) shows a planar view of rotatable filter 2673 includingthree narrow bandpass filters. The rotatable filter 2763 containsfilters 2663, 2669, 2671 corresponding to the wavelength of threedifferent substances.

For example filter 2663 is centered at 9400 nm for measuring glucose,filter 2669 is centered at 8300 nm for measuring cholesterol and filter2671 is centered at 9900 nm for measuring ethanol. Filter 2667 iscentered at between 10.5 m and 11 m and is used as a reference filter.The filter being used is in apposition with detector 2664. The filtersnot being used, for example filter 2663 rests against a solid part 2773of the probe not permeable to infrared radiation. Although only onereference filter is shown it is understood that a similar rotatablesystem with different reference filters can be used according to thesubstance being measured. Infrared detector 2664 can consist of passivedetectors such as thermopile detectors. The electrical signal generatedby detector 2664 is fed into the processor (not shown) for determinationof the concentration of the substance of interest. A variety of focusinglens and collimating means known in the art including polyethylene lensor calcium fluoride lens can be used for better focusing radiation intoinfrared detector 2664.

By applying Beer-Lambert's law, the ratio of the reference and measuredvalues is used to calculate the concentration of the substance ofinterest independent of the temperature value. One preferred method fordetermining the concentration of the substance of interest is to directthe field of view of the detector to capture radiation coming from themedial canthal area of the eye (corner of the eye), which is the hottestspot on the surface of the human body. The field of view of an infrareddetector can also be directed at the eyelid pocket lining after theeyelid is pulled away.

FIG. 104(L) shows another preferred temperature measuring system 2675 inwhich the temperature detector 2677 rests against the canthal area(inner corner of the eye) and tear duct of the eye and the body 2679 ofthe contact device rests in the eyelid pocket. FIG. 104(M) shows analternative embodiment for measurement of concentration of substancesusing far infrared thermal emission from the eye and a temperaturegradient. The contact device 2703 includes infrared sensor 2704.Infrared sensor 2704 has a superior half 2704 a exposed to ambienttemperature above the eyelid pocket and the inferior half 2704 b remainsinside the eyelid pocket measuring core temperature. Alternatively, onesensor can be placed against the skin and another one in the eyelidpocket.

FIG. 104(N) shows a device 2705 for measuring substances of interest ortemperature using a band or ring-like arrangement including both theupper and lower eyelid pockets.

FIG. 104(O) shows the pen 2706 connected to an arm 2707 at a fixeddistance. The tip of the pen or probe 2706 has an angled tip to fit withthe curvature of the sclera with a radius of approximately 11.5 mm. Thefiled of view of the pen 2706 is in accordance with the distance of theeye surface to the sensor. The arm 2707 can be used to push the lowerlid down and expose the conjunctival area to be measured. Thisfacilitates exposing the conjunctiva and provides measurement of thesame location and same distance. Fresnell lenses can be added to measuretemperature at a longer distances. An articulated arm or flexible shaftcan also be used to facilitate reaching the area of interest.

Other alternative means to determine the concentration of the substanceof interest using the conjunctiva/plasma interface includes using anactual reference cell with a known amount of the substance beingmeasured incorporated in the pen 2731 which is used as a reference. Inaddition, stimulating an enzymatic reaction to process glucose can beused. Since processing of glucose can cause an exothermic reaction, theamount of heat generated can be correlated with the amount of glucose.

FIG. 104(P) shows simultaneous measurement of temperature of the rightand left eye with a non-contact infrared system 2693. Arm 2695 carries asensor measuring temperature for the right eye which is displayed ondisplay 2701. Arm 2697 carries a sensor measuring temperature for theleft eye which is displayed on display 2669. The difference intemperature (left eye is 101° F. and right eye 97° F.) can be indicativeof a disorder. An asymmetric eye temperature also can corresponds withcarotid disease and nervous system abnormalities. Although temperaturewas used as an illustration, the device can also be used for detectingasymmetry in the concentration of chemical substances.

FIG. 104(Q1-Q4) shows a series of photographs for evaluation andmeasurement of thermal radiation from the eye and conjunctiva/plasmainterface. The images were acquired using a computerized high-resolutioninfrared imaging system which measures the far-infrared energy emittedby the eye and displays the images. In the photographs, the amount ofthermal energy goes from highest to intermediate and lowest. In theblack and white images the white digital points correspond to the areasof highest thermal energy, black indicates the coolest part and grayintermediate. The hottest external point in the human body is located inthe inner canthal area. This area corresponds to an exposed conjunctivaand reflects the thermal energy in the eyelid pocket. This is easilyobserved by looking at the eye and noticing the red area in the eye bythe nose which is continuous with the lining in the eyelid pocket.

FIGS. 104(Q1A) shows an image of the thermal energy present in the eyebefore applying a fan and cold immersion of hands FIG. 104Q1B shows theimage after applying a fan/immersion of hands in cold in order to try tocool down the conjunctiva/plasma interface Note that there is virtuallyno change in the amount of thermal energy demonstrating the stability ofthe thermal emission of the area.

FIG. 104(Q2A-B) shows black and white images with the hottest pointappearing as white dots. FIG. 104(Q2A) shows the thermal emission fromthe red superficial conjunctiva/plasma interface located by the nosewith the eyes closed. FIG. 104(Q2B) shows the enormous amount of thermalenergy present in the conjunctival area and margin of the eyelid pocket(B) with the eyes open. Note that the points are of same color andcharacteristics indicating same thermal energy present on thesessurfaces. Note that the cornea (A) is cold (dark color) in relation tothe conjunctiva (bright white points).

FIG. 104 (Q3) shows the symmetry of thermal energy between the two eyesand the hottest spot located in the canthal area. Note that theremaining portion of the face is cold in relation to the conjunctiva.There are no bright white points on the face with the exception of theinner canthal area.

FIG.104 (Q4) shows a close-up view of the lower eyelid being pulled downby the finger. This maneuver exposes the eyelid pocket lining andconjunctiva/plasma interface showing the high amount of thermal energypresent in the area. Note the great concentration of bright white pointsin the surface of the eyelid pocket representing the thermal energybeing emitted from the area. The great amount, consistency andreproducibility of thermal energy in the conjunctiva/plasma interfaceand eyelid pocket allows obtaining a high signal to noise ratio andaccurate and precise determination of the substance of interest usingfar-infrared emission from the eye.

FIG. 104(Q5) shows a close-up view of the face and eyes with thesymmetric and great amount of infrared radiation being emitted by thecorner of both eyes which are seen as bright white spots. Note that theonly place in which bright spots can be seen is in the corner of the eyeindicating the highest amount of infrared energy being radiated. Thedarker the area the lesser amount of infrared energy being emitted. Thegreat amount, consistency and reproducibility of thermal energy in thecorner of the eye allows obtaining a high signal to noise ratio andaccurate and precise determination of the substance of interest usingfar-infrared emission from the corner of the eye. Illustrative resonanceabsorption peak for some exemplary substances of interest (wavelength innm)

Albumin 2170 Bilirubin 460 Carbon dioxide 4200 Cholesterol 2300Creatinine 2260 Cytochromes 700 Ethanol 3300 Glucose 2120 Hemoglobin 600Ketones 2280 Lutetium texaphyrin 732 L-aspartyl chlorin e6 664 Oxygen770 Photoporphyrin 690 Porphyrins 350 Purlytin 664 Triglycerides 1715Urea 2190 Verteporfin 689 Water 11000

The body maintains ocular blood flow constant, whereas skin, muscle, andsplancnic blood flow varies with changing cardiac output and ambientconditions. Oxygen in the eye can continuously monitor perfusion anddetect early hemodynamic changes. In addition, the oxygen levels foundin the eyelid pocket reflects central oxygenation. The oxygen monitoringin the eye can be representative of the general hemodynamic state of thebody. Many critical conditions such as sepsis (disseminated infection)or heart problems can alter perfusion in most of the body and it is thusdifficult to evaluate adequacy of organ perfusion.

The eye though, remains with unaltered perfusion in such disease statesand can provide a good indication of the level of oxygenation. FIG.105(A) shows a simplified block diagram of ICL 2710 with oxygen sensor2712 and RF transceiver 2714 wirelessly connected to a pacemaker 2716and an internal cardiac defibrillator 2718. The contact device 2710 foroxygen monitoring can be used for activating lifesaving equipment suchas pacemakers 2716, internal cardiac defibrillators 2718, and the like.The defibrillator 2718 or pacemaker 2716 can be activated if the levelsof oxygen are within critical levels, for example during sleeping whenthe user is not capable to react to the life-threatening condition. Theactivation of the pacemaker 2716 or defibrillator 2718 is preferablydone when both the oxygen sensor 2710 and the heart tracing sensor 2720indicate a life-threatening condition. Other systems such as implantedconventional plethysmography can also work in association with the eyemonitoring systems to provide a more comprehensive monitoring.

The eye also provides a direct indication of heart beating and rhythm.FIG. 105(B) shows a tracing of heart beat achieved by using a contactdevice and transducer placed on the eye. The tracing gives a waveformcorresponding to heart rhythm that can be used to monitor cardiacarrhythmia and cardiac contractility. The beating of the heart can bedetected and a change in heart rhythm used to activate or regulatelifesaving equipment.

FIG. 105(C) shows a block diagram in which the Intelligent Contact Lens2720 is used as heart monitor and coupled to an implanted pacemaker2716, an internal cardiac defibrillator 2718, an alarm system 2722, anda medication delivery system 2724 that can deliver for instance heartmedication to increase heart contractility or medication to correct anabnormal heart rate in order to meet oxygenation and perfusion needs ofthe patient.

The monitoring system can also be used as an intraoperative awarenessdevice. The phenomenon of intraoperative awareness occurs when a patientawakes during surgery and experiences pain. The anesthetic wears off butbecause of muscle paralyzing drugs the patient, although awake, cannotreact to the pain, speak, or move. However, the eye muscles areactivated when one awakens and the reverse Bell phenomena can be used togauge how awake the patient is. The reverse Bell phenomena relates tothe eyes moving from a supero-temporal position to a straight gazeposition when the individual awakens. The monitoring function can beaccomplished by identifying the changes that occur with the movement ofthe eye when the patient is awake. For instance, a motion or pressuresensor can be encased in the contact device and transmit the informationto an external receiver. In addition, the change in rhythm as identifiedby the tracing in FIG. 105(B) can be combined with the above reverseBell phenomena monitoring means and used to gauge the degree ofanesthesia.

With-reference to FIGS. 105(D1-D7), a HTSD (Heat StimulationTransmission Device) is shown. Although the HSTD herein is described forthe eye, it is understood that the system can be used in the other partsand organs of the body. The HSTD 2711 is an arc shaped band with aradius of approximately 11.5 mm to fit in apposition to the sclera 2659.FIG. 105(D1) shows a cross-sectional view of the eye with the HSTD 2711implanted on the surface of the eye in apposition to the sclera 2659.The HSTD 2711 includes a heating element 2713, a temperature sensor 2715such as a thermocouple and a RF transceiver 2719 connected to thethermocouple 2715 by cable 2717. The heating element 2713 is locatedadjacent to the neovascular membrane 2729 being treated and located inthe most posterior part of the eye. The heating element 2713 emits heatranging from 40 to 41 degrees Celsius. This amount of heat deliveredover 12 hours restores function of abnormal vessels and closes leakingvessels with reabsorption of liquid leaking from the vessels. This HSTD2711 can be surgically implanted in the back of the eye in apposition tothe sclera 2659 or inside the sclera 2659, for treating cancer, maculardegeneration, diabetic retinopathy, neovascular membranes, veinocclusion, glaucoma, and any other vascular abnormalities present in theeye and the body. Besides surgical implantation, the HSTD can benoninvasively placed on the surface of the eye.

An LED, laser or other light sources delivering radiation in theinfrared region can also be used in the device 2711 as a substitute forheating element 2713. The use of the infrared wavelength including theuse of LEDs results in delivering radiation that is minimally absorbedby photoreceptors in the retina. The diameter of the LED, light sourceor heating element can preferably vary between 0.5 mm to 6 mm dependingon the size of the lesion being treated. A thermocouple 2715 can beincorporated to measure temperature real time which is transmitted to anexternal receiver 2725 via transceiver 2719.

The apparatus is based on the physiologic and anatomic characteristicsof the eye. The eye has the largest supply of blood per gram of tissueand has the unique ability to be overperfused when there is an increasein temperature. For each degree Celsius of increase in temperature thereis an increase of about 7% in the oxygen levels in the eye. Thisincrease in temperature causes dilation of the capillary bed andincreased delivery of oxygen and can be used in situations in whichthere is hypoxia (decreased oxygenation) such as in diabetes, vascularocclusions, carotid artery disease, and the like. A higher increase intemperature and long term exposure causing localized hyperthermia leadsto vascular sclerosis and reabsorption of liquid and can be used in thetreatment of neovascular membranes as it occurs in age-related maculardegeneration. A further increase in temperature causes obliteration ofvessels and necrosis of rapidly duplicating cells and can be used fortreating tumors.

Besides surface electrodes, one exemplary and preferred way forgenerating heat for the HSTD is by using conductive polymers withself-regulating properties. Conductive polymers are made from a blend ofspecially formulated plastics and conductive particles. At predeterminedtemperatures the polymer assumes a crystalline structure through whichthe conductive particles form low-resistance chains in the polymermaterial that carry the current. With increased temperature thepolymer's structure changes to an amorphous state breaking theconductive chains and rapidly increasing the device's resistance. Whenthe temperature returns to its preset value the polymer returns to itscrystalline state and the conductive chains reform, returning theresistance to its normal value. At the preset temperature levels, notenough heat is generated to change the polymer to an amorphous state.When there is an excess heat the resistance rapidly increases with acorresponding decrease in the current and consequent decreased heatformation.

The apparatus of the present invention allows the tissue being treatedto be maintained at a predetermined temperature. In addition minimum andmaximum temperature can be set. The internal temperature and resistancedepends on the chemical composition of that specific polymer. For anyconductive polymer, there is a current that will raise the polymer'sinternal temperature high enough to cause it to change from acrystalline to a non-crystalline or amorphous state. As current passesthrough the conductive polymer heat is generated. As the temperaturedrops, the number of electrical paths through the core increases andmore heat is produced. Conversely, as the temperature rises, the corehas fewer electrical paths and less heat is produced keeping thetemperature at a set predetermined level. The apparatus respondscontinuously to temperature increasing their heat output as thetemperature drops and decreasing heat output as the temperature rises.Such conductive polymers are available from the Raychem Corporation,Menlo Park, Calif.

The apparatus of the invention provides precisely the right amount ofheat at the predetermined location and time. The system design can beadjusted to accommodate any type of disorder ranging from lowertemperature (less heat) for treating diabetic-retinopathy to mediumrange temperature (38.5 to 40 degrees Celsius) to treat neovascularmembranes and higher temperature for treating cancer in the eye or anylocation in the body. The apparatus of the invention is low-cost andadjusts automatically to temperature changes. There is no need forspecial controls and no moving parts. Although the apparatus wasdescribed using polymers, ceramic, conductive paste, polymer thick fillsand a variety of polymeric positive temperature coefficient devices, andthe like can be used in the HSTD of the present invention. When usingsuch conductive polymers a lower cost system can be achieved. In thisembodiment the HSTD can include a power source and controller coupled tothe conductive polymer. There is no need for a temperature detector norRF transmitter.

Another preferred embodiment, besides heating, includes the use of aradioactive source. The radioactive source can also be used in thedevice 2711 as a substitute for heating element 2713. For example anactive seed such as Iodine-125 (I-125) or Paladium-103 (Pd-103) emittingx-rays and gamma rays can be used. A fiber-based delivery system fordelivering radiation which is encased in the HSTD 2711 can also be used.

Besides I-125 and Pd-103 other isotopes and Iridium can be used.Although, I-125 has a half-life of 59.61 days which would take about oneyear for complete inactivation, the device 2711 with the seed can beeasily removed at any time according to the response of the tissue.Exemplary seeds are available from North American Scientific, Inc.,Chatsworth, Calif.

The device 2711 with radioactive seeds can be used to treat neovascularmembranes, vascular abnormalities, cancers, and the like and length ofimplantation done according to the disease being treated. For treatingneovascular membranes the device 2711 should be removed in less than 7days with longer periods for treating cancer.

FIG. 105(D2) shows a side view of the arc-shaped HSTD 2711 with itselements 2713, 2715, 2719 encased in it.

FIG. 105 (D3) shows a frontal view of the HSTD 2711 shaped as a band andwith two small arms 2721 with holes 2721 a for fixating the device 2711against the sclera 2659. Suture 2725 is passed through the hole 2721 aof arms 2721 to secure the device 2711 in a stable position. Multiplearms in different positions can be incorporated for fixating the device2711 in a more stable position. The arc length of the device 2711 isdependent upon the location of the lesion being treated.

FIGS. 105(D4-D6) show exemplary steps used for implantation. The patientlooks down and a drop of anesthetic is placed on the eye. Then anincision 2723 is made in the conjunctiva and device 2711 is slid overthe sclera 2659 toward the back of the eye. While the patient is stilllooking down, a couple of sutures 2725 are placed for fixation of device2711 to the sclera 2659 using the side arms 2721.

FIG. 105(D6) shows the device 2711 and microscopic sutures covered bythe conjunctiva 2320 and the upper eyelid 2411. After completion of theprocedure the device 2711 is not visible andno discomfort elicited.After the lesion is treated the device 2711 can be easily removed withone drop of anesthetic with subsequent cutting the sutures 2725 andpulling the device 2711 out.

FIG. 105(D7) shows a frontal view of the HSTD 2711 shaped as a cross andwith two holes 2721 a for fixating the device 2711 against the sclera2659. This preferred HSTD is a low cost device only comprising theheating element 2713, cables 2717, and power source/controller 2717 a.Multiple arms in different positions can be incorporated for deliveringa more widespread heat to the organ. The arms preferably embrace theorgan for achieving an intimate apposition. The arms are shapedaccording to the shape of the organ being treated.

Besides the sensor being encased in a conventional contact lensconfiguration as described above, the sensor part can be placed in theeye and subsequent to that a polymer that solidifies when in contactwith the eye is placed the eyelid pocket. This alternative embodimentcan be used for creating the housing for the sensor in-situ, meaning inthe eye pocket.

Additional Dispensing Capabilities:

Many patients go blind even after diagnosis and treatment for thedisease has been instituted. One classic example is glaucoma. Thetreatment of glaucoma requires the patient to instill eye drops on adaily basis in order to preserve their sight. Even after beingprescribed sight-saving eye drops, patients still go blind. Sometimespatients need to instill drops several times a day for a variety ofdiseases. Studies have shown that close to 60% of patients haddifficulties with self-administration of eye drops. Current means toadminister topical ocular drugs requires skills. The patient must notonly administer the drops with a correct amount, but also master arather difficult technique.

The technique recommended and most used for instilling eye drops wasdescribed in the paper “How best to apply topical ocular medication”.The process is not simple which explains the difficulties related tousing eye drops. The steps include: bending the neck, looking up,looking away from the tip of the bottle to avoid fright reaction,pulling the lower eyelid down and away from the globe, positioning theinverted bottle over the eye but not touching any part of the eye,squeezing the bottle and placing the drop on the eye without touchingthe tip to the eye, to eyelids, or to eyelashes and yet without blinkingor lid squeezing when compressing the bottle. The problems described bypatients included: raising their arms above their heads, tilting theirheads, holding the bottle and squeezing the bottle with the arms raised,directing the bottle on top of the eye without touching the eye, fear ofhitting the eye leading the bottle to the held too high or away from theeye, involuntary blinking or closing eyes after squeezing the bottle,placing the correct number of eye drops, and poor view of the tip of thebottle.

With the dispensing ICL of the present invention, the user does not haveto bend their neck in addition to not having to perform all of the othermaneuvers described above. This ICL dispensing device and applicatorsystem of the present invention eliminates or substantially minimizesthese difficulties and the consequent vision loss that occur due toinability of instilling eye drops correctly.

The user can comfortably place the dispensing ICL on the eye accordingto the following method and steps. The dispensing ICL is placed on theeye under direct view and looking straight ahead. The user holds thehandle in the ICL, place said dispensing ICL in the edge of the lowereyelid pocket while looking at a mirror. The remainder of the dispensingICL then engages the surface of the cornea and the patient closeshis/her eye. The closure of the eye or blinking provides the actuatingforce to deform a reservoir and release the medication from thereservoir. The patient keeps the eye closed for 15 seconds to allowbetter absorption of the medication, then open the eyes, grasps thehandle and removes the dispensing ICL from the eye.

In FIG. 106(A), the Intelligent Contact Lens dispensing device 2750includes a self-contained substance source 2752 which is released by thephysical displacement of a portion of the reservoir 2760 thereofwhereupon substance 2752 is forced to the outside and directed to thesurface of the eye. The substance 2752 self-contained in the reservoircan include liquid, gel, ointment, powder, pastes, gas, and the like.

Still with reference to FIG. 106(A), the apparatus include a dispensingIntelligent Contact Lens 2750 adapted to facilitate the dispensing ofsubstances 2752 such as eye drops, and preferably actuated by eyelidmotion. The apparatus is preferably utilized as a single use and isdisposable. The Intelligent Contact Lens in FIG. 106(A) includes a mainbody 2754 to engage the surface of the eye and a reservoir 2760. Thereservoir 2760 has the distal end 2756 partially covered with threemembranes 2758, 2762, 2764. The closure-seal membranes 2758, 2762, 2764are applied to the open distal end 2756 of the reservoir 2760 facing theeye surface. Illustratively, the membrane 2764 spans a hole 2766 in theopen distal end 2756 of the reservoir 2760 to encapsulate the liquid orpowder inside said reservoir 2760. The membranes 2758, 2762, 2764 andwalls 2768 of the reservoir 2760 ensure leak-proof retention of thesubstance 2752 inside said reservoir 2760. The reservoir 2760 can bemade of elastic material which is compressible. The reservoir 2760component and surrounding main body structure 2754 is made-to bedeformable by pressure applied against said reservoir.

FIG. 106(B) shows the main body 2754 joined by a shaft 2772 which isconnected to a handle 2774. The handle 2774 is used to facilitateplacement and removal of the dispensing ICL 2750 to and from the eye.

In reference to FIG. 107(A), the actuating element to cause deformationof the reservoir 2760 with extrusion of its contents is preferablyprovided by pressure applied by the eyelid 2770 during blinking orclosure of the eye. The eyelid motion provides the most universal andnatural actuating force. Everybody without disease blinks in the samemanner. People from difference races blink in the same manner. Theprocess of blinking in a normal person does not age and a 70 year oldperson blinks in the same manner as a 20 year old. The closure of theeye or blinking produces a 10 mmHg increase in pressure and applies aforce of 25,000 dynes against the exterior surface of the main body 2754and reservoir 2760.

FIG. 107(A) also shows this squeezing pressure by the eyelid 2770 whichexceeds the bursting strength of the membrane portion 2764 and themembrane 2764 is then ruptured. FIG. 107(A) yet shows the dispensing ICL2750 partially compressed in its upper part encompassing membrane 2764by the squeezing pressure of the eyelid 2770. The liquid 2752 isexpelled from reservoir 2760 and directed toward the surface of the eyeand absorbed by the eye. The liquid permeates the cornea 2776 and can beseen in the anterior chamber 2778 of the eye.

FIG.107(B) shows the dispensing ICL 2750 completely compressed by theeyelid 2770 with the medication 2752 absorbed by the eye and present inlarge quantities in the anterior chamber 2778 of the eye. The main body2754 of the compressed dispensing ICL 2750 serves as a surface toincrease retention time.

Another advantage of the present dispensing means is the ability ofincreasing retention time by interposing a surface such as the main body2754 against the fluid 2752 which increases penetration. One importantproblem when administering topical eye drops is that the medication isdrained through the lacrimal canal and absorbed by the circulation inthe nose and throat. This is experienced when applying eye drops, whenone can taste the drops. A serious problem, including death reported inthe literature, occur due to the absorption of eye drops by thenaso-pharingeal circulation.

By increasing retention time as provided with the methods and apparatusdescribed herein, there is elimination or reduction of unwanted drainageand systemic absorption of medications designed to be used in the eye.The increased retention time and surface barrier by the main body 2754of the dispensing ICL 2750 prevents the unwanted drainage of the eyemedication. Thus, the dispensing ICL provides a much safer way for thedelivery of medications to the eye. In addition, the ICL dispensingsystem 2750 provides a more cost-effective solution. The increasedretention time increases absorption of medication by the eye, and thusless medication is wasted.

Although, the preferred embodiment includes a reservoir with membranesthat can be broken, it is understood that the dispensing function can beaccomplished without the rupture of the membrane. The pressure appliedby the eyelid during closure, of the eye can cause increased permeationof the wall and membranes to the medication present inside thereservoir. The medication can then reach the eye surface through intactwalls of the reservoir and without fracture of the seal to initiatepassage of the liquid. Although the cornea was described as a preferredembodiment, other parts in the surface of the eye can be used forplacement of the dispensing ICL with the actuation means preferablyprovided by the squeezing pressure of the eyelid. Although a permanentlyfixed shaft 2772 and handle 2774 was described, it is understood that adetachable shaft 2772 and handle 2774 can be used.

It is also understood that although reservoirs were used, a sponge-likematerial that absorbs fluid a certain predetermined amount over a setperiod of time can be used. The sponge dispensing ICL is then placed onthe eye in a similar fashion. The pressure of the eyelid during closureof the eye can then squeeze the fluid present in the sponge structure.Multiple membranes can also be used to allow the medication to be incontact with a large surface of the eye for better absorption as well asa combination of multiple membranes and a sponge part.

Although the preferred embodiment relates to using blinking as theactuating force, it is understood that squeezing of the eyelids orapplying pressure from the outside can be used as actuating means. FIG.108 shows pressure being applied by an external source 2880 such as afinger or massage motion against the closed eyelids 2770 with thedispensing ICL 2750 underneath said eyelid 2770. This alternativeembodiment can be used by patients with severe disorders of the musclesof the eyelid or with eyelid nerve damage as means to enhance pressureapplied by said diseased eyelid. Pressing with the finger or massagingthe dispensing ICL is less desirable due to the enormous variation inforce applied and risk of injury.

Although, the preferred embodiment uses a membrane that can be fracturedunder pressure, it is understood that a one way valve, single ormultiple, alone or in combination with fracturable membranes can beused. Any other means, valves, or membranes that retain the substance inthe reservoir and which release the substance upon deformation can beused in the dispensing ICL.

FIG. 109 shows a dispensing ICL 2750 with a dual reservoir 2882, 2884,for example, with two different medications including timolol gel 2886and latanoprost 2888 which are medications used for glaucoma treatment.A single or multiple reservoir configuration can be used for single ormultiple delivery of medications.

In order to facilitate placement, handles can be included and grasped byfingers or forceps for insertion without touching the main body.Alternatively the body can be made out of magnetic material and amagnetic applicator used for placement and removal of the dispensingICL. In addition, part of the main body can be made of rigid material toallow securely grasping of the dispensing ICL without touching thereservoirs.

An alternating embodiment for the dispensing ICL is shown in FIGS.110(A) and 110(B). This alternative embodiment isolates the liquid fromthe main body of the contact device engaging the eye. The apparatusincludes a liquid containing squeezable bulb 2890 joined by a conduit2892 to a main body contact device 2900 in apposition to the eye 2894. Arupturable membrane or seal 2896 contains and isolates the liquid 2752from the main body contact device 2900 and keep said liquid 2752confined to the storage bulb 2890. The contact device 2900 is connectedby a conduit 2892 to the storage bulb 2890. The contact device 2900 hasmultiple openings 2902 in its concave surface through which the liquid2752 from the conduit 2892 flows to the surface of the eye 2894. Thecontact device 2900 serves to direct the liquid 2752 to the surface ofthe eye 2894 and to increase retention time for the liquid 2752 beingapplied to the eye 2894.

In use the patient places the contact device 2900 on the surface of theeye 2894 and squeezes the bulb 2890. FIG. 10(B) shows the bulb 2890partially squeezed by pressure P to illustrate the dynamics of thedispensing process. This pressure P directs the liquid 2752 against theseal 2896 to cause its rupture and force the liquid 2752 through theconduit 2892. The liquid 2752 then travels to the contact device 2900,enters the channel 2904 and is delivered to the surface of the eye 2894,which includes the cornea and/or conjunctiva. The dimensions of bulb2890 and contact device 2900 are made to deliver the appropriate amountof medication according to the prescribed dosage by the doctor.

Although one storage area in the bulb was described, it is understoodthat multiple storage areas in the bulb can be used. Besides, thestorage bulb can be of a detachable type. The storage bulb can have twocompartments, one with air and one with liquid and a dual membrane seal.The first membrane seal is interposed between the air and liquid storageareas and the second membrane seal between the liquid storage area andthe conduit. This embodiment allows delivery of the total amount ofliquid in the storage liquid compartment as the air fills the remainderof the conduit and contact device. In addition, tubular means connectedto the storage bulb or a medication dispenser can be used to create agap in the eyelid pocket and precisely deliver the medication into saideyelid pocket. This can be done with the tubular fluid delivery meansalone or coupled to a member that facilitate positioning and/or openingof the eyelid pocket.

The reservoir with the medication can be encased in the main body duringmanufacturing or assembly of the ICL by conventional contact lensmanufacturing means. A variety of conventional manufacturing processesfor contact lens can be used including injection molding, light-curedpolymerization, casting process, sheet forming, compression, automaticor manual lathe cutting techniques, and the like. An exemplary way caninclude placement in the molding cavity of a pellet which has themedication sealed with a membrane. The polymer injected in the cavitysurrounding the pellet forms the body of the dispensing ICL. The pelletcontaining medication encased by the surrounding polymer turns into thereservoir in the dispensing ICL.

While several embodiments of the present invention have been shown anddescribed, alternate embodiments and combination of embodiments and/orfeatures will be apparent to those skilled in the art and are within theintended scope of the present invention.

1. An apparatus for noninvasive measurement of a concentration of atleast one substance from the conjunctiva, said apparatus comprising: amid-infrared radiation detector configured to detect mid-infraredradiation emitted from the conjunctiva, said-mid-infrared radiation fromsaid conjunctiva containing a radiation signature of said at least onesubstance, said mid-infrared detector producing a signal representativeof said mid-infrared radiation signature, a processor including a memorystoring a plurality of predetermined reference values and a processingcircuit for receiving said signal representative of said mid-infraredradiation signature from said conjunctiva, comparing said signalrepresentative of said mid-infrared radiation signature from saidconjunctiva with one of said plurality of reference values, anddetermining the concentration of the at least one substance based uponsaid comparison, and a display for reporting the concentration of saidat least one substance from the conjunctiva.
 2. The apparatus of claim1, wherein said at least one substance includes at least one of glucose,ethanol and cholesterol.
 3. The apparatus of claim 1, further comprisingat least one filter for selecting a radiation wavelength.
 4. Theapparatus of claim 3, wherein said at least one filter has amid-infrared bandwidth centered on about 9,400 nm corresponding to theradiation signature of glucose.
 5. The apparatus of claim 3, whereinsaid at least one filter has a mid-infrared bandwidth centered on about9,900 nm corresponding to the radiation signature of ethanol.
 6. Theapparatus of claim 3, wherein said at least one filter has amid-infrared bandwidth centered on about 8,300 nm corresponding to theradiation signature of cholesterol.
 7. The apparatus of claim 3, whereinsaid at least one filter passes mid-infrared radiation havingwavelengths between about 9,000 nanometers and about 11,000 nanometers.8. The apparatus of claim 1, wherein a cooling device is used toincrease a temperature gradient between a cold junction and a hotjunction of an infrared sensor of said mid-infrared detector.
 9. Theapparatus of claim 1, wherein said plurality of reference valuesincludes a radiation wavelength corresponding to the concentration ofsaid at least one substance.
 10. The apparatus of claim 1, furthercomprising an infrared spectrometer.
 11. The apparatus of claim 1,wherein said display includes at least one of a numerical display of avalue of said concentration and an audio device for audiblycommunicating a value of said concentration.
 12. The apparatus of claim1, further comprising a housing for the detector and the processor, saidhousing is one of a pen device and a wired handle to be held by a handof a subject so that the housing is spaced away from the conjunctiva andmeasurements are performed without contacting the conjunctiva.
 13. Theapparatus of claim 1, further comprising a housing for the detector andthe processor, said housing is a contact device for contacting theconjunctiva during measurement.
 14. Amethod for noninvasive of at leastone substance from the conjunctiva, said method comprising the steps of:detecting mid-infrared radiation emitted from said conjunctiva, saidmid-infrared radiation containing a radiation a radiation signature ofsaid at least one substance from the conjunctiva, determining theradiation signature of at least one substance from said mid-infraredradiation from said conjunctiva, and determining a concentration of saidat least one substance present in the conjunctiva from the mid-infraredradiation signature from the conjunctiva.
 15. The method of claim 14,further comprising a step of selecting a desired wavelength of saidmid-infrared radiation.
 16. The method of claim 14, wherein saidmid-infrared radiation comprises mid-infrared radiation havingwavelengths between about 9,000 nanometers and about 11,000 nanometers.17. The method of claim 14, wherein said step for determining theconcentration of said at least one substance includes the step ofcomparing the detected radiation signature from said mid-infraredradiation with a plurality of predetermined reference values.
 18. Themethod of claim 17, wherein said plurality of predetermined referencevalues includes a radiation wavelength corresponding to theconcentration of said at least one substance.
 19. The method of claim14, wherein said at least one substance includes at least one ofglucose, ethanol and cholesterol.
 20. The method of claim 14, whereinsaid mid-infrared radiation comprises mid-infrared radiation havingwavelengths between about 4,000 nanometers and about 14,000 nanometers.21. The method of claim 14, wherein said detecting step includesdetecting mid-infrared radiation from said conjunctiva without contactwith the surface of said conjunctiva.
 22. A method of determining ananalyte concentration in a tissue of a subject, the subject including aneye with an ocular surface and a conjunctiva surface, comprising thesteps: a. detecting naturally occurring mid-infrared radiation emittedfrom the conjunctiva without contact with the ocular surface using anon-invasive instrument comprising a mid-infrared detector; b. comparinga radiation signature of said mid-infrared radiation to a radiationsignature of mid-infrared radiation corresponding to an analyteconcentration; and c. analyzing said radiation signature of saidmid-infrared radiation from said subject to determine said analyteconcentration in a tissue of said subject.
 23. The method of claim 22,wherein said analyte is selected from the group consisting of metaboliccompounds or substances, carbohydrates, sugars, glucose, proteins,peptides, amino acids, fats, fatty acids, triglycerides,polysaccharides, alcohols, ethanol, toxins, hormones, vitamins,bacteria-related substances, fungus-related substances, parasite-relatedsubstances, pharmaceutical compounds, non-pharmaceutical compounds,pro-drugs, drugs, and any precursor, metabolite, degradation product orsurrogate marker.
 24. The method of claim 23, wherein said analyte isglucose.
 25. The method of claim 22, wherein said naturally occurringmid-infrared radiation comprises infrared radiation having wavelengthsbetween about 2.5 microns and about 25.0 microns.
 26. The method ofclaim 22, wherein said detecting step further comprises selecting anddetecting desired wavelengths of said naturally occurring mid-infraredradiation.
 27. The method of claim 22, wherein said comparing step andsaid analyzing step further comprise using a microprocessor.
 28. Amethod of downloading and storing a subject's measured analyteconcentration, comprising the steps of: a. measuring said analyteconcentration according to the method of claim 22, using a non-invasivemid-infrared detecting instrument having a communications interface; b.connecting said instrument through said communications interface to acomputer system having a computer processor, a computer program whichexecutes in said computer processor, and an analogous communicationsinterface; and c. downloading from said instrument to said computersystem said measured analyte concentrations.